Some drugs enhance or inhibit the activity of specific enzymes (intracellular or extracellular). The leading role in ensuring the functions of cells is played by the universal adenylate cyclase system of cells, and the effect of many drugs is associated with the activity of adenylate cyclase or phosphodiesterase enzymes that regulate the concentration of intracellular cyclic adenosine monophosphate (cAMP).
Drugs can stimulate or inhibit enzymes, interact with them to different degrees, reversibly or irreversibly, which affects the severity and duration of the pharmacological effect.
Physico-chemical effect of drugs on cell membranes
The physicochemical effect on cell membranes is a change in the transmembrane electric potential as a result of the effect on the transport of ions through the cell membrane. This is important for the activity of cells of the nervous and muscular systems: the conduction of nerve impulses through synapses is disrupted, and the electrical activity of the cells is suppressed.
Thus, antiarrhythmic, anticonvulsant drugs, agents for general anesthesia and local anesthetics act.
Direct chemical (cytotoxic) effects of drugs
Drugs can directly interact with small intracellular molecules or structures, leading to disruption of cell activity.
Antibacterial drugs, antiviral and cytostatic agents have a similar effect.
The effect of drugs may not be associated with a change in cell functions (for example, the neutralization of hydrochloric acid with antacids or the effect of oil laxatives).
Drug Selectivity
The selectivity of the action of drugs is achieved through various distribution and accumulation of drugs in organs, tissues, cells and the selectivity of their mechanism of action.
Selectivity is the ability to exert a certain desired effect and not cause other undesirable effects due to the effect on individual types or subtypes of receptors. For example, β-adrenergic blocking agents (metoprolol, atenolol), serotonin receptor antagonists (ketanserin) act on a specific subtype of the corresponding receptors, but the selectivity of such drugs is most often relative and, with an increase in the dose of the same β-adrenergic blocking agents, can be partially lost. Another approach to ensuring the relative selectivity of the action of the drug is the selective administration of the corresponding LF at the site of the desired effect (for example, intracoronary administration of nitroglycerin to patients with coronary artery disease).
There are no drugs that act selectively on a particular receptor, organ, or pathological process. The higher the selectivity of the drug, the more effective it is.
Drugs with a low selectivity of action affect many tissues, organs and systems, causing many adverse reactions. Each drug has a more or less wide spectrum of action and can cause a number of desirable or undesirable reactions.
For example, morphine, which has a pronounced analgesic activity, belongs to the group of narcotic analgesics. However, it depresses breathing, suppresses the cough reflex, has a sedative effect, causes vomiting, constipation, bronchospasm, histamine release, has an antidiuretic effect, etc.
Antineoplastic agents, acting on rapidly dividing cells, damage not only the tumor tissue, but also the bone marrow, intestinal epithelium, provoking severe adverse reactions.
The higher the selectivity of the action of drugs, the better tolerated by patients and the lower the number of adverse reactions it causes.
An example is third-generation H 2 receptor blockers, M 1 -cholinergic blockers, and H +, K + -ATPase inhibitors.
The selectivity of the drug depends on its dose. The higher it is, the less selective the drug.
So, selective β 1 -adrenergic blockers predominantly affect the myocardium, but with an increase in dose, they also affect β 2 -adrenergic receptors located in the bronchi, blood vessels, pancreas and other organs, leading to the development of undesirable reactions (bronchospasm, vasoconstriction).
The selectivity of the action of antiviral drugs, such as acyclovir, also depends on the dose: the suppression of viral DNA polymerase occurs at concentrations of the drug 3000 times lower than those that affect the DNA polymerase of human cells, therefore, acyclovir in therapeutic doses is non-toxic.
5. LOCAL AND RESORPTIVE ACTION OF MEDICINES. DIRECT AND REFLECTIVE ACTION. LOCALIZATION AND MECHANISM OF ACTION. TARGETS FOR MEDICINES. Reversible and irreversible action. SELECTIVE ACTION
5. LOCAL AND RESORPTIVE ACTION OF MEDICINES. DIRECT AND REFLECTIVE ACTION. LOCALIZATION AND MECHANISM OF ACTION. TARGETS FOR MEDICINES. Reversible and irreversible action. SELECTIVE ACTION
The action of a substance that occurs at the site of its application is called local. For example, enveloping agents cover the mucous membrane, preventing the irritation of the endings of the afferent nerves. With superficial anesthesia, applying a local anesthetic to the mucous membrane leads to the block of endings of the sensory nerves only at the site of application of the drug. However, a true local effect is extremely rare, since substances can either be partially absorbed or exert reflex effect.
The action of a substance that develops after its absorption, entry into the general bloodstream and then into the tissue, is called resorptive 2. Resorptive action
1 From English clearance- cleaning.
2 From lat. resorbeo- I absorb.
the effect depends on the route of administration medicines and their ability to cross biological barriers.
With local and resorptive action, drugs have either a direct or a reflex effect. The first is realized at the place of direct contact of the substance with the tissue. With the reflex effect of a substance, exoeroles or interceptors affect the effect and the effect is manifested by a change in the state of either the corresponding nerve centers or the executive organs. So, the use of mustard in the pathology of the respiratory system reflexively improves their trophism (essential mustard oil stimulates skin exteroceptors). The drug lobelin, administered intravenously, has an exciting effect on the chemoreceptors of the carotid glomerulus and, reflexively stimulating the center of respiration, increases the volume and frequency of respiration.
The main task of pharmacodynamics is to find out where and how drugs act, causing certain effects. Thanks to the improvement of methodological techniques, these issues are resolved not only at the systemic and organ, but also at the cellular, subcellular, molecular and submolecular levels. So, for neurotropic drugs, those structures of the nervous system are established whose synaptic formations have the highest sensitivity to these compounds. For substances that affect metabolism, the localization of enzymes in different tissues, cells and subcellular formations is determined, the activity of which changes especially significantly. In all cases, we are talking about those biological substrates, "targets" with which the drug interacts.
Receptors, ion channels, enzymes, transport systems and genes serve as “targets” for drugs.
Receptors are the active groups of macromolecules of substrates with which a substance interacts. Receptors that provide the manifestation of the action of substances are called specific.
The following 4 types of receptors are distinguished (Fig.
I. Receptors that directly control the function of ion channels. This type of receptor directly coupled to ion channels includes n-cholinergic receptors, GABA A receptors, and glutamate receptors.
II. Receptors conjugated to an effector through the G-proteins-secondary transmitters or G-proteins-ion channels system. Such receptors are available for many hormones and mediators (m-cholinergic receptors, adrenergic receptors).
III. Receptors that directly control effector enzyme function. They are directly linked to tyrosine kinase and regulate protein phosphorylation. According to this principle, insulin receptors, a number of growth factors, are arranged.
IV. Receptors that control DNA transcription. Unlike membrane receptors of types I-III, these are intracellular receptors (soluble cytosolic or nuclear proteins). Steroid and thyroid hormones interact with such receptors.
The study of receptor subtypes (Table II.1) and related effects has proved very fruitful. Among the first studies of this kind were the work on the synthesis of many β-blockers, which are widely used in various diseases of the cardiovascular system. Then, histamine H 2 receptor blockers appeared, effective in treating gastric ulcer and duodenal ulcer. Subsequently, it was synthesized
Fig.The principles of action of agonists on processes controlled by receptors.
I - a direct effect on the permeability of ion channels (n-cholinergic receptors, GABA A receptors); II - indirect effect (via G-proteins) on the permeability of ion channels or on the activity of enzymes that regulate the formation of secondary transmitters (m-cholinergic receptors, adrenergic receptors); III - a direct effect on the activity of the tyrosine kinase effector enzyme (insulin receptors, receptors of a number of growth factors); IV - effect on DNA transcription (steroid hormones, thyroid hormones).
but many other drugs acting on different subtypes of α-adrenergic receptors, dopamine, opioid receptors, etc. These studies have played a big role in creating new groups of selectively acting drugs that have been widely used in medical practice.
Considering the effect of substances on postsynaptic receptors, it should be noted the possibility of allosteric binding of substances both endogenous (e.g. glycine) and exogenous (e.g. anxiolytics of the benzodiazepine series; see chapter 11.4, Fig. 11.3) of origin. Allosteric 1 interaction with the receptor does not cause a “signal”. However, there is a modulation of the main mediator effect, which can both increase and decrease. The creation of substances of this type opens up new possibilities for regulating the functions of the central nervous system. A feature of neuromodulators of allosteric action is that they do not directly affect the main mediator transmission, but only modify it in the desired direction.
An important role for understanding the mechanisms of regulation of synaptic transmission was played by the discovery of presynaptic receptors (Table II.2). Ways of homotropic autoregulation (the action of the secreting mediator on presynaptic receptors of the same nerve endings) and heterotropic regulation (presynaptic regulation due to another mediator) of the release of mediators were studied, which made it possible to re-evaluate the features of the action of many substances. This information also served as the basis for a targeted search for a number of drugs (for example, prazosin).
1 From Greek. allos- different, different, stereos- spatial.
Table II.1Examples of some receptors and their subtypes
The affinity of a substance for a receptor, leading to the formation of a “substance-receptor” complex with it, is denoted by the term “affinity” 1. The ability of a substance when interacting with a receptor to stimulate it and cause a particular effect is called internal activity.
1 From lat. affinis- kindred.
Substances that, when interacting with specific receptors, cause changes in them that lead to a biological effect, are called agonists 1 (they also have internal activity). The stimulating effect of the agonist on receptors can lead to activation or inhibition of cell function. If an agonist interacting with receptors causes the maximum effect, it is called a complete agonist. In contrast to the latter, partial agonists interacting with the same receptors do not cause the maximum effect. Substances that bind to receptors but do not stimulate them are called antagonists 2. They have no internal activity (equal to 0). 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 with which agonists interact, then we are talking about competitive antagonistsif - other parts of the macromolecule that are not related to a specific receptor, but interconnected with it, then - noncompetitive antagonists.When a substance acts as an agonist on one subtype of receptors and as an antagonist on another, it is designated an antagonist agonist. For example, the analgesic pentazocine is an antagonist of μ and an agonist of δ and κ opioid receptors.
The "substance-receptor" interaction is carried out due to intermolecular bonds. One of the most durable bonds is covalent. It is known for a small number of drugs (α-blocker phenoxybenzamine, some anti-blast agents). Less stable is the widespread ionic bond due to the electrostatic interaction of substances with receptors. The latter is typical for ganglion blockers, curariform agents, acetylcholine. An important role is played by the van der Waals forces, which form the basis of hydrophobic interactions, as well as hydrogen bonds (Table II.3).
Table II.3.Types of interaction of substances with receptors
1 This refers to the interaction of nonpolar molecules in an aqueous medium. * 0.7 kcal (3 kJ) per CH 2 group.
Depending on the strength of the “substance-receptor” bond, a reversible action (characteristic of most substances) and irreversible (usually in the case of a covalent bond) are distinguished.
1 From Greek. agonistes- rival (agon- fight).
2 From Greek. antagonisma- struggle, rivalry (anti- against, agon- fight).
If a substance interacts only with functionally unique receptors of a certain localization and does not affect other receptors, then the action of such a substance is considered selective. So, some curariform-like agents quite selectively block end-plate cholinergic receptors, causing relaxation of skeletal muscles. In doses that have a myoparalytic effect, they have little effect on other receptors.
The basis for the selectivity of the action is the affinity (affinity) of the substance for the receptor. This is due to the presence of certain functional groups, as well as the general structural organization of the substance that is most adequate for interaction with this receptor, i.e. their complementarity. Often, the term "selective action" with good reason is replaced by the term "preferential action", since the absolute selectivity of the action of substances practically does not exist.
When evaluating the interaction of substances with membrane receptors that transmit a signal from the outer surface of the membrane to the inside, it is also necessary to take into account those intermediate links that bind the receptor to the effector. The most important components of this system are G-proteins 1, a group of enzymes (adenylate cyclase, guanylate cyclase, phospholipase C) and secondary transmitters (cAMP, cGMP, IF 3, DAG, Ca 2+). An increase in the formation of secondary transmitters leads to the activation of protein kinases, which provide intracellular phosphorylation of important regulatory proteins and the development of various effects.
Most of the links in this complex cascade can be the point of application of the action of pharmacological substances. However, such examples are still quite limited. So, in relation to G-proteins, only toxins are known that bind to them. With gs -protein cholera vibrio toxin interacts, and with Gi -protein - toxin of pertussis sticks.
There are individual substances that directly affect the enzymes involved in the regulation of the biosynthesis of secondary transmitters. So, diterpen of plant origin forskolin, used in experimental studies, stimulates adenylate cyclase (direct effect). Phosphodiesterase inhibits methylxanthines. In both cases, the concentration of cAMP inside the cell rises.
One of the important “targets” for the action of substances is ion channels. Progress in this area is largely associated with the development of methods for recording the function of individual ion channels. This stimulated not only basic research on the kinetics of ionic processes, but also contributed to the creation of new drugs that regulate ionic currents (Table II.4).
Already in the middle of the twentieth century, it was found that local anesthetics block potential-dependent Na + channels. Blockers of Na + channels include many antiarrhythmic drugs. In addition, it was shown that a number of antiepileptic drugs (diphenin, carbamazepine) also block potential-dependent Na + channels, and their anticonvulsant activity is apparently associated with this.
1 Types of some G-proteins and their functions: G S - conjugation of excitatory receptors with adenylate cyclase; G i - conjugation of inhibitory receptors with adenylate cyclase; G o - conjugation of receptors with ion channels (reduced current Ca 2+); Gq- conjugation of receptors that activate phospholipase C; G-proteins are composed of 3 subunits - α, β and γ.
Table II.4.Means affecting ion channels
In the last 30-40 years, much attention has been paid to Ca 2+ channel blockers, which disrupt the entry of Ca 2+ ions into the cell through voltage-dependent Ca 2+ channels. The increased interest in this group of substances is largely due to the fact that Ca 2+ ions are involved in many physiological processes: muscle contraction, secretory activity of cells, neuromuscular transmission, platelet function, etc.
Many drugs in this group have been very effective in treating such common diseases as angina pectoris, cardiac arrhythmias, and arterial hypertension. Widely recognized drugs such as verapamil, diltiazem, phenigidine and many others.
Activators of Ca 2+ channels, for example, dihydropyridine derivatives, also attract attention. Such substances can be used as cardiotonics, vasoconstrictor agents, substances that stimulate the release of hormones and mediators, as well as central nervous system stimulants.
Of particular interest is the search for blockers and activators of Ca 2+ channels with a predominant effect on the heart, blood vessels of different areas (brain, heart, etc.), central nervous system. There are certain prerequisites for this, since the Ca 2+ channels are heterogeneous.
In recent years, substances that regulate the function of K + channels have attracted great attention. It is shown that potassium channels are very diverse in their functional characteristics. On the one hand, this significantly complicates pharmacological studies, and on the other, it creates real prerequisites for the search for selectively active substances. Both activators and potassium channel blockers are known.
Activators of potassium channels contribute to their opening and the release of K + ions from the cell. If this occurs in smooth muscles, hyperpolarization of the membrane develops and muscle tone decreases. Thanks to this mechanism, minoxidil and diazoxide are used as antihypertensive agents, as well as the antianginal drug nicorandil.
Potassium channel blockers are of interest as antiarrhythmic drugs (amiodarone, ornide, sotalol).
Blockers of ATP-dependent potassium channels in the pancreas increase insulin secretion. According to this principle, antidiabetic drugs of the sulfonylurea group (chlorpropamide, butamide, etc.) act.
The stimulating effect of aminopyridines on the central nervous system and neuromuscular transmission is also associated with their blocking effect on potassium channels.
Thus, exposure to ion channels underlies the effects of various drugs.
An important "target" for the action of substances are enzymes. The possibility of exposure to enzymes that regulate the formation of secondary transmitters (e.g., cAMP) has already been noted. It has been established that the mechanism of action of non-steroidal anti-inflammatory drugs is due to inhibition of cyclooxygenase and a decrease in prostaglandin biosynthesis. Inhibitors of the angiotensin-converting enzyme (captopril and others) are used as antihypertensive agents. Anticholinesterase agents that block acetylcholinesterase and stabilize acetylcholine are well known.
The anti-blast agent methotrexate (a folic acid antagonist) blocks dihydrofolate reductase, preventing the formation of tetrahydrofolate, which is necessary for the synthesis of a purine nucleotide, thymidylate. The antiherpetic drug acyclovir, turning into acyclovir triphosphate, inhibits viral DNA polymerase.
Another possible “target” for the action of drugs is transport systems for polar molecules, ions, and small hydrophilic molecules. These include the so-called transport proteins that carry substances across the cell membrane. They have recognition sites for endogenous substances. These sites can interact with drugs. So, tricyclic antidepressants block the neuronal uptake of norepinephrine. Reserpine blocks the deposition of norepinephrine in vesicles. One of the significant achievements is the creation of proton pump inhibitors in the gastric mucosa (omeprazole, etc.), which have been shown to be highly effective in gastric and duodenal ulcers, as well as in hyperacid gastritis.
Recently, in connection with the decoding of the human genome, intensive studies have been carried out related to the use as a target genes.Undoubtedly gene therapyis one of the most important areas of modern and future pharmacology. The idea of \u200b\u200bsuch therapy is to regulate the function of genes whose etiopathogenetic role has been proven. The basic principles of gene therapy are to increase, decrease or turn off gene expression, as well as to replace a mutant gene.
The solution to these problems became real thanks to the ability to clone chains with a given nucleotide sequence. The introduction of such modified chains is aimed at normalizing the synthesis of proteins that determine this pathology, and, accordingly, at restoring impaired cell function.
A central problem in the successful development of gene therapy is the delivery of nucleic acids to target cells. Nucleic acids must enter plasma from extracellular spaces, and then, passing through cell membranes, penetrate the nucleus and incorporate into the chromosomes. It is proposed to use some viruses (for example, retroviruses, adenoviruses) as transporters, or vectors. Moreover, with the help of genetic engineering, vector viruses lose their ability to replicate, i.e. no virions are formed from them. Other transport systems have been proposed — DNA complexes with liposomes, proteins, plasmid DNA, and other microparticles and microspheres.
Naturally, the incorporated gene must function for a sufficiently long time, i.e. gene expression must be persistent.
Potential gene therapy concerns many inherited diseases. These include immunodeficiency states, some types of liver pathology (including hemophilia), hemoglobinopathies, lung diseases (e.g. cystic fibrosis), muscle tissue (Duchenne muscular dystrophy), etc.
Research is underway on a broad front to clarify potential ways to use gene therapy to treat tumor diseases. These possibilities are to block the expression of oncogenic proteins; in the activation of genes capable of inhibiting tumor growth; in stimulating the formation of special enzymes in tumors that convert prodrugs into compounds toxic only to tumor cells; increasing the resistance of bone marrow cells to the inhibitory effect of anti-blastoma agents; enhancing immunity against cancer cells, etc.
In cases when it becomes necessary to block the expression of certain genes, a special technology of the so-called antisense (antisense) oligonucleotides is used. The latter are relatively short chains of nucleotides (from 15–25 bases) that are complementary to the nucleic acid region where the target gene is located. As a result of interaction with the antisense oligonucleotide, the expression of this gene is suppressed. This principle of action is of interest in the treatment of viral, tumor and other diseases. The first drug from the group of antisense nucleotides, vitraven (fomivirsen), is applied topically for retinitis caused by cytomegalovirus infection. This type of drug has appeared to treat myeloid leukemia and other blood diseases. They are undergoing clinical trials.
Currently, the problem of using genes as targets for pharmacological effects is mainly in the stage of basic research. Only a few promising substances of this type undergo preclinical and initial clinical trials. However, there is no doubt that in this century many effective means for gene therapy of not only hereditary, but also acquired diseases will appear. These will be fundamentally new drugs for the treatment of tumors, viral diseases, immunodeficiency states, hematopoiesis and blood coagulation disorders, atherosclerosis, etc.
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GOU VPO "Nizhny Novgorod State Medical Academy of the Ministry of Health and Social Development of the Russian Federation"
Department of General and Clinical Pharmacology
Action of drugs
1. Local and resorptive effects of drugs
The action of a substance that occurs at the site of its application is called local. For example, enveloping agents cover the mucous membrane, preventing the irritation of the endings of the afferent nerves. With superficial anesthesia, applying a local anesthetic to the mucous membrane leads to the block of endings of the sensory nerves only at the site of application of the drug. However, a true local effect is extremely rare, since substances can either be partially absorbed or have a reflex effect.
The action of a substance that develops after its absorption, entry into the general bloodstream and then into the tissue, is called resorptive. The resorptive effect depends on the route of administration of drugs and their ability to penetrate biological barriers.
2. Direct and reflex action
With local and resorptive action, drugs have either a direct or a reflex effect. The first is realized at the place of direct contact of the substance with the tissue. With a reflex effect, substances affect extero- or interoceptors and the effect is manifested by a change in the state of either the corresponding nerve centers or the executive organs. So, the use of mustard in the pathology of the respiratory system reflexively improves their trophism (essential mustard oil stimulates skin exteroceptors). The drug lobelin, administered intravenously, has an exciting effect on the chemoreceptors of the carotid glomerulus and, reflexively stimulating the center of respiration, increases the volume and frequency of respiration.
reversible selective drug pharmacodynamics
3. Localization and mechanism of action
The main task of pharmacodynamics is to find out where and how drugs act, causing certain effects. Thanks to the improvement of methodological techniques, these issues are solved not only at the systemic and organ, but also at the cellular, subcellular, molecular and submolecular levels. So, for neurotropic drugs, those structures of the nervous system are established whose synaptic formations have the highest sensitivity to these compounds. For substances that affect metabolism, the localization of enzymes in different tissues, cells and subcellular formations is determined, the activity of which changes especially significantly. In all cases, we are talking about those biological substrates, "targets" with which the drug interacts.
4. “Targets” for drugs
Receptors, ion channels, enzymes, transport systems and genes serve as “targets” for drugs.
Receptors are the active groups of macromolecules of substrates with which a substance interacts. Receptors that provide the manifestation of the action of substances are called specific.
The following 4 types of receptors are distinguished (Fig.
I. Receptors that directly control the function of ion channels. This type of receptor directly coupled to the ion channels includes n-cholinergic receptors, GABAA receptors, glutamate receptors.
II. Receptors conjugated to an effector through the G-proteins-secondary transmitters or G-proteins-ion channels system. Such receptors are available for many hormones and mediators (m-cholinergic receptors, adrenergic receptors).
III. Receptors that directly control effector enzyme function. They are directly linked to tyrosine kinase and regulate protein phosphorylation. According to this principle, insulin receptors, a number of growth factors, are arranged.
IV. Receptors that control DNA transcription. Unlike membrane receptors of types I-III, these are intracellular receptors (soluble cytosolic or nuclear proteins). Steroid and thyroid hormones interact with such receptors.
Considering the effect of substances on postsynaptic receptors, it should be noted the possibility of allosteric binding of substances of both endogenous (e.g. glycine) and exogenous (e.g. anxiolytics benzodiazepine series) origin. Allosteric interaction with the receptor does not cause a “signal”. However, there is a modulation of the main mediator effect, which can both increase and decrease. The creation of substances of this type opens up new possibilities for regulating the functions of the central nervous system. A feature of neuromodulators of allosteric action is that they do not directly affect the main mediator transmission, but only modify it in the desired direction.
An important role for understanding the mechanisms of regulation of synaptic transmission was played by the discovery of presynaptic receptors. Ways of homotropic autoregulation (the action of the secreting mediator on presynaptic receptors of the same nerve ending) and heterotropic regulation (presynaptic regulation due to another mediator) of the release of mediators were studied, which made it possible to re-evaluate the features of the action of many substances. This information also served as the basis for a targeted search for a number of drugs (for example, prazosin).
The affinity of a substance for a receptor, leading to the formation of a “substance-receptor” complex with it, is indicated by the term “affinity”. The ability of a substance when interacting with a receptor to stimulate it and cause a particular effect is called internal activity.
5. Reversible and irreversible action. selective action
Depending on the strength of the “substance-receptor” bond, a reversible action (characteristic of most substances) and irreversible (usually in the case of a covalent bond) are distinguished.
If a substance interacts only with functionally unique receptors of a certain localization and does not affect other receptors, then the action of such a substance is considered selective. So, some curariform-like agents quite selectively block the cholinergic receptors of the end plates, causing relaxation of the skeletal muscles. In doses that have a myoparalytic effect, they have little effect on other receptors.
The basis for the selectivity of the action is the affinity (affinity) of the substance for the receptor. This is due to the presence of certain functional groups, as well as the general structural organization of the substance that is most adequate for interaction with this receptor, i.e. their complementarity. Often, the term "selective action" with good reason is replaced by the term "preferential action", since the absolute selectivity of the action of substances practically does not exist.
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