To treat diseases, substances are used that differ both in nature and in the strength of their action. Along with potent, toxic substances (strychnine, arsenic, sublimate) used in therapy and usually called poisons, other, more harmless means are also used. However, it is very difficult to distinguish medicinal substances into poisonous and non-toxic. For example, table salt, which we consume daily with food, taken in large quantities (200.0-300.0), can cause poisoning, ending in death.
The same medicinal substance, depending on the dose used, the state of the body and other conditions, can either have a therapeutic effect, that is, serve as a medicine, or be a poison that causes severe harm to the body and even causes the death of the latter. Pharmacology, which studies the effect of substances on the body primarily for therapeutic purposes, is closely related to toxicology - the science of the toxic effects of various substances.
Medicinal substances can have different effects on the body, which depends on the characteristics of the action of the substance, the method of its use, the dose and the condition of the body. Depending on the characteristics of each substance, different drugs are used for different purposes:
some as sleeping pills, others as cardiac drugs, others as local anesthetics, etc. Depending on the route of administration, the nature of the action of the drug often changes. For example, magnesium sulfate, when taken orally, has a laxative effect, and when administered intravenously or subcutaneously, it has a narcotic effect.
The effect may also vary depending on the dose. Rhubarb powder in doses of 0.3-0.5 or more has a laxative effect, and c. smaller doses cause the opposite effect - a fixing effect. The state of the body has a particularly great influence on the effect of substances, which will be discussed in more detail later.
The effect of drugs may be exciting or depressing. The initial stages of the stimulating effect are usually called a tonic, or stimulating, effect. For example, strychnine, a substance that excites the central nervous system, in small doses increases its tone and thus contributes to more efficient functioning of the whole organism and the functioning of individual organs. In large doses, strychnine causes strong stimulation of the central nervous system, manifested by strong convulsive contractions of all muscles of the body.
The inhibitory effect of medicinal substances used in small doses manifests itself in suppression, suppression of the function of individual organs or systems of the body. The same substances in large doses cause a paralyzing effect or complete paralysis. For example, hypnotic substances in therapeutic doses depress the central nervous system and cause a condition, but in large, toxic doses they can cause paralysis of the central nervous system and death.
Excitement resulting from exposure to large doses of (toxic or lethal) stimulants can also develop into a state of paralysis.
For various medicinal purposes, medicinal substances are usually used in doses that cause a reversible effect. Reversible is an effect when, after stopping the use of medicinal substances, the body, as well as the organs exposed to these substances, return to their normal state. For example, the pupil of the eye dilates under the influence of atropine sulfate, but then, after removing this substance from the body, it returns to its previous size.
Less commonly used irreversible the effect of medicinal substances, an example of which is the cauterization of warts or other growths with silver nitrate (lapis) or acids. In this case, first of all, the death of the cells of these growths is achieved and, thus, their destruction. In this case, an irreversible reaction is observed.
The following types of action of medicinal substances are distinguished.
General action, i.e., an effect on the entire body, and this can occur after the substance is absorbed and enters the bloodstream or reflexively. During panic attacks, the entire body experiences stress, and complex treatment is needed that affects the body as a whole. In addition to drug treatment for panic attacks, psychotherapy is also important.
Local action, which is a type of general action and manifests itself mainly at the site of application of the medicinal substance until it is absorbed. In this case, one should take into account a number of reflexes that occur at the site of application of the medicine and have a corresponding effect.
Reflex action. Based on the principle of Pavlovian nervism, the reflex should be considered the main form of nervous regulation of the physiological functions of our body. The reflex is carried out by transmitting excitation from the periphery along the sensory nerves to the central nervous system, and from there through the motor nerves to various organs and centers of the body, for example, the exciting effect resulting from inhaling ammonia during fainting. In this case, irritation of the sensitive nerve endings of the nasopharyngeal mucosa occurs, which is transmitted to the central nervous system with a corresponding reflex response - excitation of vital centers. I.P. Pavlov attached extremely great importance to reflex mechanisms under the action of various substances. At the same time, he especially emphasized the importance of interoreception (the occurrence of a reflex from interoreceptors of various tissues and organs) along with extrareception (the occurrence of a reflex from the skin and mucous membranes).
Selective action. I. II. Pavlov believed that all medicinal substances have a specific pharmacological effect inherent in each of them. At the same time, he also pointed out the selectivity of the action of these substances. If a substance has a particularly strong effect on any organ or system, while the effect on other organs and the entire body is not so pronounced, then such an effect is called selective.
Side effect. Sometimes, along with the therapeutic effect of a substance, an undesirable, from the clinician’s point of view, so-called side effect appears (for example, skin rashes when giving bromides, iodides).
Based on the basic Pavlovian principles about the integrity of the body, the leading role of the central nervous system and the corrective influence of the cerebral cortex, the effect of medicinal substances should be considered as affecting the entire body as a whole, and only depending on the most pronounced effect on individual systems or organs , we can talk about their predominantly local or selective action, etc. Treatment with various drugs is most often etiotropic and symptomatic.
Etiotropic treatment. Etiotropic (from the Greek words aethia - cause and tropo - direct), or -causal treatment is the effect of medicinal substances on the cause of a given disease. For example, gastric lavage in case of poisoning or the prescription of saline laxatives, which prevent the absorption of poison and promote faster removal from the body. This type of action also includes the effect of medicinal substances on the causative agent of the disease, for example, treatment with quinine for malaria, novarsenol for syphilis, sulfonamides for pneumonia, salicylates for acute articular rheumatism, etc.
Symptomatic treatment. Symptomatic treatment is the effect of medicinal substances aimed at eliminating or intensifying certain symptoms of the disease, for example, the use of antipyretic substances in a very febrile patient to lower the temperature and improve poor health associated with severe overheating of the body; prescribing pyramidon for headaches to eliminate it; giving expectorants for better removal of sputum, etc.
The action of a substance that occurs at the site of its application is called local. For example, enveloping agents coat the mucous membrane, preventing irritation of afferent nerve endings. With superficial anesthesia, application of a local anesthetic to the mucous membrane leads to a block of sensory nerve endings only at the site of application of the drug. However, a truly 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 tissues is called resorptive. The resorptive effect depends on the route of administration of drugs and their ability to penetrate biological barriers.
With local and resorptive action, drugs have either a direct or reflex effect. The first is realized at the site of direct contact of the substance with the tissue. During reflex action, substances affect exteroceptors or interoceptors and the effect is manifested by a change in the state of either the corresponding nerve centers or executive organs. Thus, the use of mustard plasters for pathologies of the respiratory organs reflexively improves their trophism (essential mustard oil stimulates skin exteroceptors). The drug lobeline, administered intravenously, has an exciting effect on the chemoreceptors of the carotid glomerulus and, reflexively stimulating the respiratory center, increases the volume and frequency of breathing.
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 levels, but also at the cellular, subcellular, molecular and submolecular levels. Thus, for neurotropic drugs, those structures of the nervous system are identified 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, the activity of which changes especially significantly, is determined. In all cases, we are talking about those biological “target” substrates with which the drug interacts.
Receptors, ion channels, enzymes, transport systems and genes serve as “targets” for drugs.
Receptors are active groups of macromolecules of substrates with which a substance interacts. Receptors that ensure the manifestation of the action of substances are called specific.
Principles of action of agonists on processes controlled by receptors. I - direct effect on the permeability of ion channels (H-cholinergic receptors, GABAA receptors); II - indirect influence (through 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 - direct effect on the activity of the effector enzyme tyrosine kinase (insulin receptors, receptors of a number of growth factors); IV - influence on DNA transcription (steroid hormones, thyroid hormones).
The following are distinguished: 4 types of receptors
I. Receptors that directly control the function of ion channels. This type of receptors directly coupled to ion channels includes H-cholinergic receptors, GABA A receptors, and glutamate receptors.
II. Receptors coupled to the effector through the “G-proteins-secondary transmitters” or “G-proteins-ion channels” system. Such receptors are available for many hormones and mediators (M-cholinergic receptors, adrenergic receptors).
III. Receptors that directly control the function of the effector enzyme. They are directly associated with tyrosine kinase and regulate protein phosphorylation. The receptors for insulin and a number of growth factors are designed according to this principle.
IV. Receptors that control DNA transcription. Unlike membrane receptors of types I-III, these are intracellular receptors (soluble cytosolic or nuclear proteins). Steroid and thyroid hormones interact with such receptors.
The study of receptor subtypes (Table II.1) and their associated effects has been very fruitful. The first studies of this kind include work on the synthesis of many β-blockers, widely used in various diseases of the cardiovascular system. Then histamine H2 receptor blockers appeared - effective drugs for the treatment of gastric and duodenal ulcers. Subsequently, many other drugs were synthesized that act on different subtypes of α-adrenergic receptors, dopamine, opioid receptors, etc. These studies played a major role in the creation of new groups of selectively active medicinal substances, which are widely used in medical practice.
When considering the effect of substances on postsynaptic receptors, it should be noted the possibility of allosteric binding of substances of both endogenous (for example, glycine) and exogenous (for example, benzodiazepine anxiolytics) origin. Allosteric interaction with the receptor does not produce a “signal.” However, there is a modulation of the main mediator effect, which can either be strengthened or weakened. The creation of substances of this type opens up new possibilities for regulating the functions of the central nervous system. A feature of allosteric neuromodulators is that they do not have a direct effect on the main neurotransmitter transmission, but only modify it in the desired direction.
The discovery of presynaptic receptors played an important role in understanding the mechanisms of regulation of synaptic transmission (Table II.2). The pathways of homotropic autoregulation (the effect of a releasing 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).
Table II.1 Examples of some receptors and their subtypes
| Receptors | Subtypes |
| Adenosine receptors | A 1, A 2A, A 2B, A 3 |
| α 1 -Adrenoreceptors | α 1A, α 1B, α 1C |
| α 2 -Adrenoreceptors | α2A, α2B, α2C |
| β-Adrenergic receptors | β 1, β 2, β 3 |
| Angiotensin receptors | AT 1, AT 2 |
| Bradykinin receptors | B 1, B 2 |
| GABA receptors | GABA A, GABA B, GABA C |
| Histamine receptors | H1, H2, H3, H4 |
| Dopamine receptors | D 1, D 2, D 3, D 4, D 5 |
| Leukotriene receptors | LTB 4, LTC 4, LTD 4 |
| M-cholinergic receptors | M 1, M 2, M 3, M 4 |
| N-cholinergic receptors | Muscular type, neuronal type |
| Opioid receptors | µ, δ, κ |
| Prostanoid receptors | DP, FP, IP, TP, EP 1, EP 2, EP 3 |
| Purine receptors P | P 2X , P 2Y , P 2Z , P 2T , P 2U |
| Excitatory amino acid receptors (ionotropic) | NMDA, AMPA, kainate |
| Neuropeptide Y receptors | Y 1, Y 2 |
| Atrial natriuretic peptide receptors | ANPA, ANPB |
| Serotonin receptors | 5-HT 1(A-F) , 5-HT 2(A-C) , 5-HT 3 , 5-HT 4 , 5-HT 5(A-B) , 5-HT 6 , 5-HT 7 |
| Cholecystokinin receptors | CCK A, CCK B |
Table II.2 Examples of presynaptic regulation of mediator release by cholinergic and adrenergic endings
The affinity of a substance for a receptor, leading to the formation of a “substance-receptor” complex with it, is designated by the term “affinity”. The ability of a substance, when interacting with a receptor, to stimulate it and cause one or another effect is called internal activity.
Substances that, when interacting with specific receptors, cause changes in them leading to a biological effect are called agonists (they have internal activity). The stimulating 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, it is called 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. 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 antagonists, if - other parts of the macromolecule that are not related to a specific receptor, but are interconnected with it, then - o non-competitive antagonists. When a substance acts as an agonist on one receptor subtype and as an antagonist on another, it is designated an agonist-antagonist. For example, the analgesic pentazocine is an antagonist of the μ- and agonist of the δ- and κ-opioid receptors.
There are also so-called nonspecific receptors, not functionally related to specific ones. These include blood plasma proteins, connective tissue mucopolysaccharides, etc., with which substances bind without causing any effects. Such receptors are sometimes called “silent” or designated as “sites of loss” of substances. However, it is appropriate to call only specific receptors receptors; nonspecific receptors are more correctly designated as sites of nonspecific binding.
The “substance-receptor” interaction is carried out due to intermolecular bonds. One of the strongest types of bonds is covalent. It is known for a small number of drugs (α-blocker phenoxybenzamine, some anti-blastoma substances). Less stable is the common ionic bond, which occurs due to the electrostatic interaction of substances with receptors. The latter is typical for ganglion blockers, curare-like drugs, and acetylcholine. An important role is played by 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 the receptor
1 This refers to the interaction of non-polar molecules in an aqueous environment
* 0.7 kcal (3 kJ) per CH 2 group
Depending on the strength of the “substance-receptor” bond, a distinction is made between reversible action (characteristic of most substances) and irreversible action (usually in the case of a covalent bond).
If a substance interacts only with functionally unambiguous receptors of a certain location and does not affect other receptors, then the action of such a substance is considered selective. Thus, some curare-like drugs quite selectively block the cholinergic receptors of the end plates, causing relaxation of skeletal muscles. In doses that have a myoparalytic effect, they have little effect on other receptors.
The basis for selectivity of action is the affinity (affinity) of the substance to the receptor. This is due to the presence of certain functional groups, as well as the general structural organization of the substance, which is most adequate for interaction with a given receptor, i.e. their complementarity. Often the term “selective action” is rightfully replaced by the term “preferential action”, since absolute selectivity of the action of substances practically does not exist.
When assessing the interaction of substances with membrane receptors that transmit a signal from the outer surface of the membrane to the inner one, it is necessary to take into account those intermediate links that connect the receptor with the effector. The most important components of this system are G-proteins, a group of enzymes (adenylate cyclase, guanylate cyclase, phospholipase C) and secondary transmitters (cAMP, cGMP, IP 3, DAG, Ca 2+). Increased formation of secondary transmitters leads to the activation of protein kinases, which ensure 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 currently quite limited. Thus, in relation to G proteins, only the toxins that bind to them are known. Vibrio cholerae toxin interacts with the G s protein, and the toxin of the whooping cough bacillus interacts with the G i protein.
There are certain substances that have a direct effect on enzymes involved in the regulation of the biosynthesis of secondary transmitters. Thus, the plant-derived diterpene forskolin, used in experimental studies, stimulates adenylate cyclase (direct action). Phosphodiesterase is inhibited by methylxanthines. In both cases, the concentration of cAMP inside the cell increases.
One of the important “targets” for the action of substances are 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 fundamental research devoted to the study of the kinetics of ionic processes, but also contributed to the creation of new drugs that regulate ionic currents (Table II.4).
Already in the late 50s, it was established that local anesthetics block voltage-gated Na + channels. Na+ channel blockers also include many antiarrhythmic drugs. In addition, it has been shown that a number of antiepileptic drugs (diphenin, carbamazepine) also block voltage-gated Na + channels and their anticonvulsant activity is apparently associated with this.
In the last 30 years, much attention has been paid to Ca 2+ channel blockers, which disrupt the entry of Ca 2+ ions into the cell through voltage-gated Ca 2+ channels. The increased interest in this group of substances is largely due to the fact that Ca 2+ ions take part in many physiological processes: muscle contraction, secretory activity of cells, neuromuscular transmission, platelet function, etc.
Many drugs in this group have proven to be very effective in the treatment of such common diseases as angina pectoris, cardiac arrhythmias, and arterial hypertension. Drugs such as verapamil, diltiazem, phenigidine and many others have received widespread recognition.
Table II.4. Agents affecting ion channels
| Na+ CHANNEL LIGANDS Na+ channel blockers Local anesthetics (lidocaine, novocaine) Antiarrhythmic drugs (quinidine, novocainamide, ethmozine) Na + channel activators Veratridine (alkaloid, hypotensive effect) |
Ca 2+ CHANNEL LIGANDS Ca 2+ channel blockers Antianginal, antiarrhythmic and antihypertensive drugs (verapamil, phenigidine, diltiazem) Ca 2+ channel activators Wow K 8644 (dihydropyridine, cardiotonic and vasoconstrictor effects) |
K+ CHANNEL LIGANDS K+ channel blockers An agent that facilitates neuromuscular transmission (pimadine) Antidiabetic agents (butamide, glibenclamide) Activators of K + channels Antihypertensive drugs (minoxidil, diazoxide) |
Activators of Ca 2+ channels, for example, dihydropyridine derivatives, also attract attention. Such substances can find use as cardiotonics, vasoconstrictors, substances that stimulate the release of hormones and mediators, as well as central nervous system stimulants. There are no such drugs for medical use yet, but the prospects for their creation are quite real.
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.), and the central nervous system. There are certain prerequisites for this, since Ca 2+ channels are heterogeneous.
In recent years, substances that regulate the function of K + channels have attracted much attention. It has been shown that potassium channels are very diverse in their functional characteristics. On the one hand, this significantly complicates pharmacological research, and on the other, it creates real prerequisites for the search for selectively active substances. Both activators and blockers of potassium channels are known.
Activators of potassium channels promote their opening and the release of K+ ions from the cell. If this occurs in smooth muscles, then hyperpolarization of the membrane develops and muscle tone decreases. Thanks to this mechanism, minoxidil and diazoxide, used as antihypertensive agents, act.
Voltage-gated potassium channel blockers are of interest as antiarrhythmic agents. Amiodarone, ornid, and sotalol appear to have a blocking effect on potassium channels.
Blockers of ATP-dependent potassium channels in the pancreas increase insulin secretion. Antidiabetic drugs of the sulfonylurea group (chlorpropamide, butamide, etc.) operate according to this principle.
The stimulating effect of aminopyridines on the central nervous system and neuromuscular transmission is also associated with their blocking effect on potassium channels.
Thus, effects on ion channels underlie the action of various drugs.
Enzymes are an important “target” for the action of substances. The possibility of influencing enzymes that regulate the formation of secondary transmitters (for example, cAMP) has already been noted. It has been established that the mechanism of action of nonsteroidal anti-inflammatory drugs is due to inhibition of cyclooxygenase and a decrease in prostaglandin biosynthesis. Angiotensin-converting enzyme inhibitors (captopril, etc.) are used as antihypertensive drugs. Anticholinesterase agents that block acetylcholinesterase and stabilize acetylcholine are well known.
The anti-blastoma drug methotrexate (folic acid antagonist) blocks dihydrofolate reductase, preventing the formation of tetrahydrofolate, necessary for the synthesis of the 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 transport substances across the cell membrane. They have recognition sites for endogenous substances that can interact with drugs. Thus, 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 shown high effectiveness in gastric and duodenal ulcers, as well as in hyperacid gastritis.
Recently, in connection with the deciphering of the human genome, intensive research has been carried out related to the use of genes. There is no doubt that gene therapy is one of the most important areas of modern and future pharmacology. The idea of such therapy is to regulate the function of genes whose etiopathogenetic role has been proven. The basic principles of gene therapy boil down to increasing, decreasing or turning off gene expression, as well as replacing a mutant gene.
The solution to these problems has become possible 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.
The central problem Successful development of gene therapy involves the delivery of nucleic acids to target cells. Nucleic acids must pass from extracellular spaces into the plasma, and then, after passing through cell membranes, penetrate the nucleus and be incorporated into chromosomes. It has been proposed to use some viruses (for example, retroviruses, adenoviruses) as transporters or vectors. At the same time, with the help of genetic engineering, vector viruses are deprived of the ability to replicate, i.e. no new virions are formed from them. Other transport systems have also 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 opportunities for gene therapy concern many hereditary diseases. These include immunodeficiency conditions, certain types of liver pathology (including hemophilia), hemoglobinopathies, lung diseases (for example, cystic fibrosis), muscle tissue (Duchenne muscular dystrophy), etc.
Research is underway on a broad front to elucidate potential ways to use gene therapy to treat tumor diseases. These capabilities include blocking the expression of oncogenic proteins; in the activation of genes that can suppress tumor growth; in stimulating the formation of special enzymes in tumors that convert prodrugs into compounds that are toxic only to tumor cells; increasing the resistance of bone marrow cells to the inhibitory effects of anti-blastoma drugs; increasing immunity against cancer cells, etc.
In cases where there is a need to block the expression of certain genes, a special technology of so-called antisense (antisense) oligonucleotides is used. The latter are relatively short chains of nucleotides (of 15-25 bases), which are complementary to the zone of nucleic acids where the target gene is located. As a result of interaction with an 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 was created - Vitraven (fomivirzen), used topically for retinitis caused by cytomegalovirus infection. Drugs of this type have appeared for the treatment of myeloid leukemia and other blood diseases. They are undergoing clinical trials.
Currently, the problem of using genes as targets for pharmacological action is mainly at the stage of fundamental research. Only a few promising substances of this type undergo preclinical and early 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 conditions, hematopoietic and blood clotting disorders, atherosclerosis, etc.
Thus, the possibilities for drug targeting are very diverse.
In pharmacology, the following types of action of medicinal substances are distinguished:
· Local action. This is the action of a drug at the site of its application before absorption into the blood. For example, the effect of enveloping agents, local anesthetic (pain-relieving) effect when applying solutions of local anesthetics to the mucous membranes. For the purpose of local action, various dosage forms are used: powders, moisturizers, ointments, solutions, etc. Local action in its pure form occurs, but rarely, since part of the substance is still absorbed into the blood or causes reflex reactions.
· Resorptive action. This is the effect of drugs after absorption into the blood and penetration into tissues, regardless of the route of its introduction into the body. This is how most drugs work.
· General cellular action. This is the action of medicinal substances aimed at all cells of the body.
· Selective action is associated with the ability of drugs to accumulate in individual tissues or with the unequal sensitivity of cellular receptors to different drugs. For example, cardiac glycosides selectively affect the heart, and antipsychotics affect the central nervous system; some curare-like substances cause selective blockade of cholinergic receptors of motor nerves and relaxation of skeletal muscles, and in therapeutic doses they have almost no effect on other receptors (for example, dithylin).
· General action- this is when medicinal substances do not have a pronounced selective effect (antibiotics).
· Direct effect of the drug manifests itself in the tissues with which it directly contacts. This action is sometimes called the primary pharmacological reaction.
· Indirect action is a response to the primary pharmacological reaction of other organs. For example, cardiac glycosides, by enhancing contractions of the heart (direct effect), improve blood circulation and the function of other organs, such as the kidneys and liver (indirect effect).
· Reflex action is a type of indirect action in which the nervous system (reflex arc) is involved. It can occur due to the resorptive and local action of drugs. For example, intravenous administration of cititon reflexively stimulates breathing; mustard plaster applied to the skin reflexively improves the function of internal organs.
· Main and side effects. The main thing is understood as the main, desired effect of the medicine that the doctor is counting on. A side effect is usually undesirable and causes complications. For example, the main thing for morphine is its analgesic effect, and its ability to cause euphoria and addiction is regarded as a significant drawback. The side effect may be positive. For example, caffeine has a stimulating effect on the central nervous system and also increases heart function. Side effects may also be undesirable (negative). Some laxatives cause pain in the intestines when they act. For some drugs that have multifaceted pharmacological properties, the main and side effects may change places depending on the specific purpose of using such a drug.
· Reversible action is a temporary pharmacological effect that ceases after the drug is removed from the body or after its destruction. For example, after anesthesia, the function of the central nervous system is completely restored.
· Irreversible action is expressed in deep structural disturbances of cells and their death, caused, for example, by cauterization of warts with silver nitrate, or irreversible inhibition of the enzyme acetylcholinesterase by organophosphorus compounds.
Questions for self-control
2. Relationship between pharmacology and other sciences.
3. History of the development of science.
4. Scientific directions of pharmacology.
5. Sources and routes of obtaining medicinal substances.
6. General patterns of interaction of medicinal substances with the body.
7. The reactivity of the body, its role in the development of the disease.
8. Enteral routes of drug administration and their comparative characteristics.
9. Parenteral routes of administration of medicinal substances and their comparative characteristics.
10. Advantages and disadvantages of enteral and parenteral routes of administration.
11. What questions does pharmacokinetics study in the section of general pharmacology?
12. Mechanisms of absorption of drugs from the stomach and intestines.
13. What is characteristic of passive diffusion of drugs through cell membranes.
14. What is characteristic of active transport of drugs through cell membranes.
15. Distribution of drugs in the body.
16. Concept of biotransformation.
17. Mechanisms of biotransformation of drugs in the liver.
18. Ways of removing drugs from the body.
19. What is bioavailability and how is it determined.
20. What questions does pharmacodynamics study in the section of general pharmacology?
21. Main targets of action of drugs.
22. Types of action of medicinal substances.
List of used literature
1. Rabinovich M.I. General pharmacology: Textbook. 2nd ed., rev. and additional / M.I. Rabinovich, G.A. Nozdrin, I.M. Samorodova, A.G. Nozdrin - St. Petersburg: Lan Publishing House, 2006. - 272 p.
2. Sedov Yu.D. Technique for administering medicinal substances to animals / Yu.D. Sedov. – Rostov n/D: Phoenix, 2014. – 93 p.
3. Subbotin V.M. Veterinary pharmacology / V.M. Subbotin, I.D. Alexandrov – M.: KolosS, 2004. – 720 p.
4. Sokolov V.D. Pharmacology / V.D. Sokolov - St. Petersburg: Lan Publishing House, 2010. – 560 p.
5. Tolkach, N.G. Veterinary pharmacology / N.G. Tolkach, I.A. Yatusevich, A.I. Yatusevich, V.V. Petrov. – Minsk: Information Computing Center of the Ministry of Finance, 2008. – 685 p.
6. Pharmacology. – M.: VINITI, 2000 – 2009.
7. Kharkevich D.A. Pharmacology: Textbook / D.A. Kharkevich. - 9th ed., revised, additional. and corr. - M.: GEOTAR - Media, 2006. - 736 p.
1. Introduction 3
2. History of the development of pharmacology 5
3. Scientific directions of pharmacology 10
4. Sources and ways of obtaining medicinal substances 12
5. General patterns of drug interactions
substances with the body 15
6. The reactivity of the body, its role in the development of the disease and
reactions to medicine 17
7. Routes of administration of drugs into the body 17
8. Pharmacokinetics 22
8.1. Absorption of drugs 23
8.2. Distribution of drugs in the body 27
8.3. Biotransformation of drugs in the body 29
8.4. Removal of drugs from the body 34
8.5. The concept of drug bioavailability 37
9. Pharmacodynamics 39
9.1. Main targets of action of drugs 40
9.2. Types of action of medicinal substances 53
10. Questions for self-control 55
11. List of references 56
- 1) LOCAL ACTION - the action of a substance that occurs at the site of its application. Example: the use of local anesthetics - introducing a solution of dicaine into the conjunctival cavity. Using a 1% novocaine solution for tooth extraction. This term (local action) is somewhat arbitrary, since truly local action is observed extremely rarely, due to the fact that substances can be partially absorbed or have a reflex effect.
- 2) REFLECTOR ACTION - this is when a medicinal substance acts on the reflex pathways, that is, it affects extero- or interoreceptors and the effect is manifested by a change in the state of either the corresponding nerve centers or executive organs. Thus, the use of mustard plasters for pathologies of the respiratory organs improves their trophism reflexively (essential mustard oil stimulates exteroceptors of the skin). The drug cititon (a respiratory analeptic) has a stimulating effect on the chemoreceptors of the carotid glomerulus and, reflexively stimulating the respiratory center, increases the volume and frequency of breathing. Another example is the use of ammonia in case of fainting (ammonia), which reflexively improves cerebral circulation and tones the vital centers.
- 3) RESORPTIVE ACTION - this is when the effect of a substance develops after its absorption (resorption - absorption; lat. - resorbeo - absorb), entering the general bloodstream, then into the tissues. The resorptive effect depends on the route of administration of the drug and its ability to penetrate biological barriers. If a substance interacts only with functionally unambiguous receptors of a certain localization and does not affect other receptors, the action of such a substance is called SELECTIVE. Thus, some curare-like substances (muscle relaxants) quite selectively block the cholinergic receptors of the end plates, causing relaxation of skeletal muscles. The action of the drug prazosin is associated with a selective effect that blocks postsynaptic alpha-one adrenergic receptors, which ultimately leads to a decrease in blood pressure. The basis for the selectivity of the action of a drug (selectivity) is the affinity (affinity) of the substance for the receptor, which is determined by the presence in the molecule of these substances of certain functional groups and the general structural organization of the substance, the most adequate for interaction with these receptors, that is, COMPLEMENTARY.
GENERAL CHARACTERISTICS OF THE EFFECT OF DRUGS ON THE BODY
Despite the abundance of medicines, all the changes they cause in the body have a certain commonality and uniformity. Based on the concept of reaction norm, there are 5 types of changes caused by pharmacological agents (N.V. Vershinin):
- 1) toning (increasing function to normal);
- 2) excitement (increased function beyond normal);
- 3) a calming effect (sedative), that is, a decrease in increased function to normal;
- 4) depression (decrease in function below normal);
- 5) paralysis (cessation of function). The sum of the tonic and stimulating effects is called the restorative effect.
MAIN EFFECTS OF DRUGS
First of all, they distinguish:
- 1) physiological effects, when drugs cause changes such as an increase or decrease in blood pressure, heart rate, etc.;
- 2) biochemical (increased levels of enzymes in the blood, glucose, etc.). In addition, there are BASIC (or main) and
NON-MAIN (minor) effects of drugs. THE MAIN EFFECT is the one on which the doctor bases his calculations when treating a given (!) patient (analgesics - for an analgesic effect, antihypertensives - to lower blood pressure, etc.).
NON-MAIN, or non-main effects, otherwise additional, those that are inherent in a given drug, but the development of which in a given patient is not necessary (non-narcotic analgesics - in addition to the analgesic effect, they cause an antipyretic effect, etc.). Non-major effects may include DESIRED and UNDESIRABLE (or SIDE) effects.
Example. Atropine - relaxes the smooth muscles of internal organs. However, at the same time, it simultaneously improves conductivity in the AV node of the heart (with heart block), increases the diameter of the pupil, etc. All these effects must be considered individually in each specific case.
FACTORS AFFECTING THE EFFECT OF DRUGS
- 1) First of all, you need to remember the pharmacokinetic factors inherent in each drug. This has already been mentioned above, let me only remind you that we are talking about its rate of absorption or absorption, biotransformation, excretion (of a drug, a drug).
- 2) The second group of factors is physiological.
- a) Age. Indeed, everyone is well aware that the patient’s sensitivity to drugs changes with age. Even in this regard, the following stood out:
- - perinatal pharmacology;
- - pediatric pharmacology;
- - geriatric pharmacology;
- - reproductive pharmacology;
- b) Weight of the patient. It is known that the larger the mass, the higher the dose. Therefore, drugs are dosed in (mg/kg).
- c) Gender. Different sensitivity is revealed in men and women to certain substances, for example, to nicotine, alcohol, etc., which is explained by differences in metabolism, differences in the specific gravity of the fat layer, etc.
- c) The state of the body. The effect of drugs on the body after significant physical activity will be different than without it.
- e) Biological rhythms (daily, monthly, seasonal, annual, and now even population) have the most serious impact on the action of drugs in the body. 3) Pathological factors (for example, the level of hormonal activity). So, with Graves' disease, toxic doses of morphine are easier to tolerate, but the sensitivity of the myocardium to adrenaline increases. 1 0The effect of cardiac glycosides on blood circulation appears only against the background of heart failure. The effect of drugs changes significantly with hypo- and hyperthermia, with infectious diseases, with changes in the functional state of the central nervous system, etc.).
- 4) Genetic factors. It is known that the absence of the enzyme glucose-6-phosphate dehydrogenase (G-6-PDH) in thalassemia makes it impossible to prescribe antimalarial drugs such as primaquine. Insufficiency of the enzyme butyrylcholinesterase in the blood, which occurs in one in 2,500 people, is the cause of prolonged muscle relaxation following the administration of dithiline.
- 5) Suggestibility of patients or placebo effect. In this regard, the antianginal effect of placebo drugs, for example, reaches 40% and up to 81% of the placebo effect occurs from the injection route of drug administration. This is probably why the use of vitamin preparations, tonics, and tranquilizers is largely due to this effect.
- 6) Dose of medicine. The effect of drugs is determined to a very large extent by their dose. A dose is the amount of a drug intended for one dose (usually referred to as a single dose). Not only the effectiveness of treatment, but also the safety of the patient depends on the dose of the drug. At the end of the 18th century, William Withering wrote: “Poison in small doses is the best medicine; useful medicine in too large a dose is poison.” This is all the more true in our time, when extremely active drugs have been introduced into medical practice, the dosages of which are measured in fractions of a milligram.
The dose is indicated in grams or fractions of a gram. For a more accurate dosage of drugs, calculate their amount per 1 kg of body weight (or per 1 sq. m of body area), for example, 1 mg/kg; 1 mcg/kg, etc. The doctor needs to be oriented not only to the dose calculated for a single dose (pro dosi), but also to the daily dose (pro die).
The minimum doses at which drugs cause the initial biological (therapeutic) effect are called threshold, or minimally effective (therapeutic) doses. In practical medicine, average therapeutic doses are most often used, in which drugs provide the necessary optimal pharmacotherapeutic effect. If, when they are prescribed to a patient, the effect is not sufficiently pronounced, the dose is increased to the highest therapeutic dose. Higher therapeutic doses can be one-time or daily. The highest single dose is the maximum amount of a drug that can be administered once without harm to the patient. These doses are used rarely, in extreme cases (in an urgent, emergency situation). Average therapeutic doses are usually 1/3-1/2 of the highest single dose.
The highest therapeutic doses of toxic and potent substances are given in the State Pharmacopoeia of the USSR. In some cases, for example, when using chemotherapy drugs, the dose of the drug per course of treatment (course dose) is indicated. If there is a need to quickly create a high concentration of a drug in the body (sepsis, cardiovascular failure), then use the first dose, the so-called loading dose, which exceeds all subsequent ones. There are also toxic (having dangerous effects) and lethal doses.
It is important for the doctor to know one more characteristic, namely the concept of the breadth of the therapeutic effect of the drug. The breadth of therapeutic action is understood as the distance, the range from the minimally therapeutic to the minimally toxic dose. Naturally, the greater this distance, the safer this drug is.
1/20 dose x number of years of the child.
To quantitatively characterize and evaluate the effectiveness of a new pharmacological agent, as a rule, two standard comparisons are used - either with a placebo or with an analo drug
gical type of action, which is one of the most effective means in this group.
A placebo (dummy) is an indifferent substance in a dosage form that imitates a specific pharmacological or drug. The use of placebo is necessary in the presence of: a) the effect of conjecture, the influence of personality, expectation and bias on the part of the patient or researcher; b) spontaneous changes in the course of the disease, symptoms, as well as phenomena not related to treatment.
Placebo is a Latin term meaning "I can give you pleasure."
The placebo effect is an effect caused not by the specific pharmacodynamic properties of a drug for a given pathology, but by the FACT OF USE of drugs, which has a psychological effect. Placebo drugs are usually pharmacologically inert, containing inactive substances like starch or lactose. Placebos are used in clinical studies in order to establish the effect of suggestion on the part of both the patient and the doctor, especially if drugs intended for the treatment of bronchial asthma, hypertension, angina pectoris, and coronary artery disease are being studied. In such cases, the placebo drug should not differ in color and other physical properties (smell, taste, shape) from the active drug. A placebo is more effective when both the doctor and the patient are less informed about it.
EXAMPLE. In case of coronary heart disease (CHD), if we prescribe an active drug to one group of patients with ischemic heart disease, and a placebo to the other, then in 40% of patients in the second group, angina attacks are stopped.
The most pronounced placebo effect (up to 81%) is observed when it is administered by injection. Potions and pills are less effective.
In the literature devoted to drug effects on a patient, the term PHARMACOTHERAPY (PT) is often heard. Pharmacotherapy is a branch of pharmacology that studies the treatment of patients with medications.
The following types of pharmacotherapy are distinguished:
- 1) ETIOTROPIC - an ideal type of pharmacotherapy. This type of PT is aimed at eliminating the cause of the disease. Examples of etiotropic PT can be the treatment of infectious patients with antimicrobial agents (benzylpenicillin for streptococcal pneumonia), the use of antidotes in the treatment of patients with poisoning by toxic substances.
- 2) PATHOGENETIC PHARMACOTHERAPY - aimed at eliminating or suppressing the mechanisms of disease development. Most currently used drugs belong specifically to the group of pathogenetic PT drugs. Antihypertensive drugs, cardiac glycosides, antiarrhythmic, anti-inflammatory, psychotropic and many other drugs have a therapeutic effect by suppressing the corresponding mechanisms of disease development.
- 3) SYMPTOMATIC THERAPY - aimed at eliminating or limiting individual manifestations of the disease. Symptomatic medications include painkillers that do not affect the cause or mechanism of development of the disease. Antitussives are also a good example of symptomatic remedies. Sometimes these drugs (elimination of pain during myocardial infarction) can have a significant impact on the course of the main pathological process and at the same time play the role of pathogenetic therapy.
- 4) REPLACEMENT PHARMACOTHERAPY is used for deficiency of natural nutrients. Replacement therapy includes enzyme preparations (Pancreatin, Panzinorm, etc.), hormonal medications (insulin for diabetes, thyroidin for myxedema), vitamin preparations (vitamin D, for example, for rickets). Replacement therapy drugs, without eliminating the cause of the disease, can ensure the normal existence of the body for many years. It is no coincidence that such a severe pathology as diabetes is considered a special lifestyle among Americans.
- 5) PREVENTIVE THERAPY is carried out to prevent diseases. Preventative drugs include some antiviral drugs (for example, during a flu epidemic - rimantadine), disinfectants and a number of others. The use of anti-tuberculosis drugs such as isoniside can also be considered preventive PT. A good example of preventative therapy is the use of vaccines.
CHEMOTHERAPY should be distinguished from pharmacotherapy. If PT deals with two participants in the pathological process, namely the drug and the macroorganism, then with chemotherapy there are already 3 participants: the drug, the macroorganism (the patient) and the causative agent of the disease.
Speaking about doses, we first of all pointed to allopathic doses, as opposed to homeopathic ones. Therefore, a few words about HOMEOPATHY. The term "homeopathy" is derived from two Greek words: homois - similar and pathos - suffering, disease. Literally, homeopathy is translated as a similar, similar disease. The founder of homeopathy, the German scientist Samuel Hahnemann, in his famous book “The Organon of the Medical Art or the Basic Theory of Homeopathic Treatment,” outlined the basic principles of this science at the beginning of the 19th century (1810). There are several principles, but 2 of them are basic:
- 1) This is the law of similarity, which states that the treatment of diseases must be carried out with a similar, similar means. According to this principle, Hahnemann advises "to imitate nature, which sometimes cures a chronic disease through another adjoining disease." Therefore, “against a disease that can be cured (mainly chronic), a medicinal substance should be used that can cause another, most similar artificial disease, and the first one will be cured.” Similia similibus (like like). For example, jaundice should be treated with yellow, etc.
- 2) The second principle is to treat with super-small doses. The dilutions of medicines used by homeopaths are calculated in several orders of magnitude, sometimes reaching dozens: 10 in the fifth; 10 in the tenth; 10 to the eighteenth power or more (that is, millionths or more of a gram). To explain the effect of using medicinal substances in high dilutions, Hahnemann put forward a speculative concept: “Small doses are distinguished by their special spiritual power, greater activity, and ability to penetrate the affected organs and tissues.”
It is not known what about the special spiritual power, but scientific life in the last decade has presented very serious evidence for the validity of Hahnemann's assertion. For example, the experiments of the Frenchman Jacques Becveniste, carried out by him with dilution of substances by 10 to the eightieth power, showed that water molecules have a “memory” for the presence of a given substance, causing a certain physiological effect. If this noted fact is confirmed in the near future, that is, if it is established whether water molecules are a source of information, we will certainly stand at the foundations of a great discovery that can explain the therapeutic effectiveness of homeopathic remedies.
Next, we will consider the section concerning PHARMACOLOGICAL ASPECTS OF THE TOXIC EFFECT OF DRUGS, namely TOXICOLOGY OF DRUGS. Toxicology of drugs is a branch of pharmacology that studies the toxic effects of these drugs. However, now it is more correct to talk about undesirable reactions of the human body to medications. This fact has been known for a long time; a wealth of factual material has been accumulated indicating that adverse reactions of varying degrees can occur when taking almost all medications.
There are many classifications of side effects of drugs and complications of pharmacotherapy, although none of them is perfect. However, based on the pathogenetic principle, all undesirable effects or reactions can be divided into 2 types:
- 1) adverse reactions associated with
- a) drug overdose
- b) poisoning;
- 2) toxic reactions associated with the pharmacological properties of drugs.
Overdose usually occurs when using high doses of drugs. Overdose occurs especially often when taking medications that have a small breadth of therapeutic action. For example, toxicity is difficult to avoid when using aminoglycoside antibiotics (streptomycin, kanamycin, neomycin). These drugs cause vestibular disorders and deafness when treated in doses that are not much higher than therapeutic ones. For some drugs, it is simply impossible to avoid toxic complications (antitumor, cytotoxic drugs), which damage all rapidly dividing cells and suppress the bone marrow while simultaneously effectively affecting the growth of tumor cells.
In addition, overdose may be associated not only with the use of high doses, but also with the phenomenon of cumulation (cardiac glycosides).
Poisoning can be accidental or intentional. Intentional poisonings usually occur with suicidal intent (to kill oneself). In the Omsk region, the most common poisoning in the overall structure of poisonings is poisoning with cauterizing liquids, followed by drug poisoning in second place. These are, first of all, poisoning with sleeping pills, tranquilizers, FOS, alcohol, carbon monoxide.
Despite the difference in etiological factors, measures of assistance at the stages of medical assistance are fundamentally similar.
These principles are:
1) FIGHTING UNABSORBED POISON FROM THE GASTROINTESTINAL TRACT. Most often this is required in case of oral poisoning. Most often, acute poisoning is caused by ingestion of substances. A mandatory and emergency measure in this regard is gastric lavage through a tube even 10-12 hours after poisoning. If the patient is conscious, gastric lavage is carried out using a large amount of water and subsequent induction of vomiting. Vomiting is caused mechanically. In an unconscious state, the patient's stomach is lavaged through a tube. It is necessary to direct efforts to the adsorption of the poison in the stomach, for which activated carbon is used (1 tablespoon orally, or 20-30 tablets at a time, before and after gastric lavage). The stomach is washed several times every 3-4 hours until the substance is completely cleared.
Vomiting is contraindicated in the following cases:
- - in comatose states;
- - in case of poisoning with corrosive liquids;
- - in case of poisoning with kerosene, gasoline (possibility of bicarbonate pneumonia with necrosis of lung tissue, etc.).
If the victim is a small child, then it is better to use saline solutions in small volumes (100-150 ml) for rinsing.
It is best to remove poison from the intestines using saline laxatives. Therefore, after washing, you can introduce 100-150 ml of a 30% solution of sodium sulfate, or even better, magnesium sulfate, into the stomach. Saline laxatives are the most powerful, acting quickly throughout the intestines. Their action obeys the laws of osmosis, so they stop the action of the poison within a short period of time.
It is good to give astringents (tannin solutions, tea, bird cherry), as well as enveloping agents (milk, egg whites, vegetable oil).
If poison comes into contact with the skin, it is necessary to rinse the skin thoroughly, preferably with cork water. If toxic substances enter the lungs, inhalation should be stopped by removing the victim from the poisoned atmosphere.
When a toxic substance is administered subcutaneously, its absorption from the injection site can be slowed by injecting an epinephrine solution around the injection site, as well as cooling the area (ice on the skin at the injection site).
2) The second principle of assistance in acute poisoning is the INFLUENCE ON THE ABSORBED POISON, REMOVAL OF IT FROM THE BODY.
In order to quickly remove toxic substances from the body, forced diuresis is used first of all. The essence of this method is to combine increased water load with the introduction of active, powerful diuretics. We flood the body by drinking plenty of fluids to the patient or administering various intravenous solutions (blood replacement solutions, glucose, etc.). The most commonly used diuretics are FUROSEMIDE (Lasix) or MANNITOL. Using the method of forced diuresis, we seem to “wash” the patient’s tissues, freeing them from toxic substances. This method only manages to remove only free substances that are not associated with proteins and blood lipids. It is necessary to take into account the electrolyte balance, which when using this method can be disturbed due to the removal of a significant amount of ions from the body.
In acute cardiovascular failure, severe renal dysfunction and the risk of developing cerebral or pulmonary edema, forced diuresis is contraindicated.
In addition to forced diuresis, hemodialysis and peritoneal dialysis are used, when blood (hemodialysis, or artificial kidney) passes through a semi-permeable membrane, freeing itself from toxic substances, or the peritoneal cavity is “washed” with a solution of electrolytes.
METHODS OF EXTRACORPORAL DETOXIFICATION. A successful detoxification method that has become widespread is the method of HEMOSORPTION (lymphosorption). In this case, toxic substances in the blood are adsorbed on special sorbents (granulated carbon coated with blood proteins, allospleen). This method allows you to successfully detoxify the body in case of poisoning with neuroleptics, tranquilizers, FOS, etc. The hemosorption method removes substances that are difficult to remove by hemodialysis and peritoneal dialysis.
BLOOD REPLACEMENT is used when bloodletting is combined with donor blood transfusion.
3) The third principle of combating acute poisoning is to REMOVAL THE ABSORBED POISON by introducing ANTAGONISTS and ANTIDOTES.
Antagonists are widely used for acute poisoning. For example, atropine for poisoning with anticholinesterase drugs, FOS; nalorphine - in case of morphine poisoning, etc. Typically, pharmacological antagonists competitively interact with the same receptors as the substances that caused the poisoning. In this regard, the creation of SPECIFIC ANTIBODIES (monoclonal) in relation to substances that are especially often the cause of acute poisoning (monoclonal antibodies against cardiac glycosides) looks very interesting.
For the specific treatment of patients with chemical poisoning, ANTIDOTE THERAPY is effective. ANTIDOTS are means used to specifically bind a poison, neutralizing, inactivating poisons either through chemical or physical interaction.
Thus, for poisoning with heavy metals, compounds are used that form non-toxic complexes with them (for example, unithiol for arsenic poisoning, D-penicillamine, desferal for poisoning with iron preparations, etc.).
4) The fourth principle is to carry out SYMPTOMATIC THERAPY. Symptomatic therapy is especially important for poisoning with substances that do not have special antidotes.
Symptomatic therapy supports vital functions: BLOOD CIRCULATION and BREATHING. Cardiac glycosides, vasotonics, agents that improve microcirculation, oxygen therapy, and respiratory stimulants are used. Convulsions are eliminated with injections of sibazon. For cerebral edema, dehydration therapy (furosemide, mannitol) is performed. analgesics are used and the acid-base state of the blood is corrected. If breathing stops, the patient is transferred to artificial ventilation with a set of resuscitation measures.
Next, we will focus on the SECOND TYPE OF ADVERSE REACTIONS, that is, unwanted reactions associated with the pharmacological properties of drugs. Side effects of drugs occur in 10-20% of outpatients, and 0.5-5% of patients require hospitalization to correct drug disorders. These undesirable, from the point of view of pathogenesis, reactions can be: a) DIRECT and b) associated with ALTERED SENSITIVITY of the patient’s body.
Let's analyze DIRECT TOXIC REACTIONS. They are called direct because the drugs directly, directly have a toxic effect on the functional system. For example, aminoglycoside antibiotics (streptomycin, kanamycin, gentamicin) exhibit NEUROTOXICITY, causing a toxic effect on the hearing organ (ototoxicity) and the vestibular apparatus. In addition, this class of antibiotics has toxicity in relation to behavioral reactions, manifested by lethargy, apathy, lethargy, and drowsiness.
Medicines may cause DIRECT GELATOTOXIC REACTIONS. For example, fluorotane (an anesthetic), when used repeatedly in a short period of time, can have a pronounced toxic effect, including acute yellow degeneration of the liver.
Direct toxic effects can be realized by NEPHROTOXICITY. Mycinic aminoglycoside antibiotics have this effect. When prescribing drugs of this series, the patient needs constant monitoring of the status of urine tests (protein, blood in the urine, etc.).
The next direct toxic effect is ULCEROGENIC (ulcer-forming). For example, the prescription of salicylates, glucocorticoids, and the antihypertensive drug reserpine leads to ulceration of the gastric mucosa, which must be taken into account when prescribing these classes of drugs, especially to patients already suffering from peptic ulcer disease.
Direct toxic effects can be expressed in EMBRYOTOXICITY. Let me remind you that embryotoxic is an adverse effect of drugs that is not associated with a violation of organogenesis and occurs before 12 weeks of pregnancy. And the toxic effect of drugs in the later period of pregnancy is called FETOTOXIC. It is necessary to remember this effect when prescribing medications to pregnant women, giving them pharmacotherapy only according to strict indications.
Examples: 1) the administration of streptomycin to pregnant women can lead to deafness in the fetus (damage to the VIII pair of cranial nerves); 2) tetracyclines negatively affect bone development in the fetus; 3) in a mother suffering from morphine addiction, the newborn may also suffer from physical dependence on morphine.
Medicines may have TERATOGENICITY, that is, such a damaging effect on the differentiation of tissues and cells that leads to the birth of children with various anomalies. For example, the use of THALIDOMIDE, which has a pronounced teratogenic effect, as a sedative and hypnotic, led to the birth in Western Europe of several thousand children with various deformities (phocomelia - flipper-like limbs; amelia - absence of limbs; facial hemangions, gastrointestinal anomalies).
To study the teratogenic effect of substances, the effect of drugs on animals is studied, although there is no direct correlation about the effect of drugs on animals and humans. For example, for the same thalidomide, teratogenicity in an experiment on mice was detected at a dose of 250-500 mg/kg, and in humans it turned out to be 1-2 mg/kg.
The first trimester (especially the period 3-8 weeks of pregnancy), that is, the period of organogenesis, is considered the most dangerous in terms of teratogenic effects. During these periods, it is especially easy to cause a severe abnormal development of the embryo.
When creating new drugs, one should also keep in mind the possibility of such serious negative effects as CHEMICAL MUTAGENICITY and CARCINOGENICITY. MUTAGENICITY is the ability of substances to cause persistent damage to the germ cell, but especially to its genetic apparatus, which manifests itself in a change in the genotype of the offspring. CARCINOGENICITY is the ability of substances to cause the development of malignant tumors. Estrogens contribute to the development of breast cancer in women of childbearing age.
Mutagenic and teratogenic effects may take months or even years to appear, making it difficult to detect their true activity. Teratogenicity is inherent in antineoplastic drugs, corticosteroids, androgens, and alcohol. Cyclophosphamide and some hormonal agents have a carcinogenic effect.
Adverse reactions when using medications can be expressed by the development of DRUG DEPENDENCE or, more generally, DRUG ADDICTION. There are several main signs of drug addiction.
- 1) This is the presence of MENTAL DEPENDENCE, that is, a condition when the patient develops an irresistible mental attraction to repeated administration of a medicinal substance, for example, a drug.
- 2) PHYSICAL DEPENDENCE - this term refers to the presence of severe physical ailment in a patient without repeated injection of a medicinal substance, in particular a drug. When the administration of a drug that has caused drug dependence is abruptly stopped, the phenomenon of DEPRIVATION or ABSTINENCE develops. Fear, anxiety, melancholy, and insomnia appear. Motor restlessness and aggressiveness may occur. Many physiological functions are impaired. In severe cases, withdrawal can be fatal.
- 3) Development of TOLERANCE, that is, addiction. Other types of undesirable effects caused by the properties of the drugs themselves are disorders associated with changes in the patient’s immunobiological system when taking highly active drugs. For example, the use of broad-spectrum antibiotics can manifest itself as a change in the normal bacterial flora of the body (intestines), resulting in the development of superinfection, dysbacteriosis, and candidiasis. Most often, the lungs and intestines are involved in these processes.
Corticosteroid therapy and immunosuppressive therapy weaken the immune system, resulting in an increased risk of developing infectious diseases, primarily of an opportunistic nature (pneumocystis, cytomegalovirus, etc.).
This subgroup of reactions comes in two types:
- 1) ALLERGIC REACTIONS;
- 2) IDIOSYNCRASY. It should be said that negative effects associated with allergic reactions occur very often in medical practice. Their frequency is increasing all the time. They occur regardless of the dose of the administered drug, and immune mechanisms participate in their formation. Allergic reactions can be of 2 types: IMMEDIATE TYPE HYPERSENSITIVITY, HNT - associated with the formation of antibodies of the IgE and IgG4 classes) and SLOW DOWN (accumulation of sensitized T-lymphocytes and macrophages) types.
The clinical picture is very diverse: urticaria, skin rashes, angioedema, serum sickness, bronchial asthma, fever, hepatitis, etc. But the main thing is the possibility of developing anaphylactic shock. If the development of allergic reactions requires at least two contacts of the patient with a medicinal substance, then the development of IDIOSYNCRASIS - intolerance to medicinal substances upon initial contact with a xenobiotic, is always associated with some kind of GENETIC DEFECT, usually expressed by the absence or extremely low activity of the enzyme. For example, the use of the antimalarial drug primaquine in individuals with a genetic enzymopathy (act. g-6-FDG deficiency) causes the formation of quinone, which has a hemolytic effect. In the presence of this fermentopathy, it is dangerous to prescribe drugs that are oxidizing agents, as this can lead to hemolysis of red blood cells and drug-induced hemolytic anemia (aspirin, chloramphenicol, quinidine, primaquine, furadonine).
A FEW WORDS ABOUT THE CREATION OF NEW MEDICINES, EVALUATION OF DRUGS AND THEIR NOMENCLATURE. The progress of pharmacology is characterized by the continuous search and creation of new drugs. Drug discovery begins with research by chemists and pharmacologists, whose creative collaboration is absolutely essential in the discovery of new drugs. At the same time, the search for new funds is developing in several directions.
The main route is the CHEMICAL synthesis of drugs, which can be implemented in the form of DIRECTED synthesis or have an EMPIRICAL route. If directed synthesis is associated with the reproduction of nutrients (insulin, adrenaline, norepinephrine), the creation of antimetabolites (PABA-sulfonamides), the modification of molecules of compounds with known biological activity (changes in the structure of acetylcholine - the gonglioblektor hygronium), etc., then the empirical path consists of either from random finds, or search through screening, that is, sifting various chemical compounds for pharmacological activity.
One example of empirical findings is the case of the discovery of a hypoglycemic effect when using sulfonamides, which subsequently led to the creation of sulfonamide synthetic perforal antidiabetic agents (butamide, chlorpropamide).
Another option for the empirical route to creating drugs is the SCREENING METHOD, which is also very labor-intensive. However, it is inevitable, especially if a new class of chemical compounds is being studied, the properties of which, based on their structure, are difficult to predict (ineffective way). And here the computerization of scientific research currently plays a huge role.
Currently, drugs are obtained mainly through directed chemical synthesis, which can be carried out a) by similarity (introduction of additional chains, radicals) b) by complementarity, that is, correspondence to any receptors of tissues and organs.
In the arsenal of medicines, in addition to synthetic drugs, a significant place is occupied by preparations and individual substances from MEDICINAL RAW MATERIALS of plant or animal origin, as well as from various minerals. These are primarily galenic and novogalenic drugs, alkaloids, and glycosides. Thus, morphine, codeine, papaverine are obtained from opium, reserpine from Rauflphia serpentine, and cardiac glycosides - digitoxin, digoxin - from foxglove; from a number of endocrine glands of cattle - hormones, immunoactive drugs (insulin, thyroidin, tactivin, etc.).
Some medicines are waste products of fungi and microorganisms. An example is antibiotics. Medicinal substances of plant, animal, microbial, and fungal origin often serve as the basis for their synthesis, as well as subsequent chemical transformations and the production of semi-synthetic and synthetic drugs.
The pace of drug creation is accelerating through the use of genetic engineering methods (insulin, etc.).
A new drug, having passed through all these “sieves” (study of pharmacoactivity, pharmacodynamics, pharmacokinetics, study of side effects, toxicity, etc.) is allowed for clinical trials. The method of “blind control”, the placebo effect, the method of double “blind control” is used here, when neither the doctor nor the patient knows when the placebo is used. Only a special commission knows. Clinical trials are conducted on humans, and in many countries this is done on volunteers. Here, of course, a lot of legal, deontological, moral aspects of the problem arise, which require their clear development, regulation and approval of laws in this regard.
Preferanskaya Nina Germanovna
Associate Professor, Department of Pharmacology, Faculty of Pharmacy, First Moscow State Medical University named after. THEM. Sechenova, Ph.D.
The appearance of undesirable side reactions when using the drug is facilitated by:
- Incorrectly selected therapeutic dose, without taking into account the individual characteristics of the patient, his concomitant diseases, age, weight and height.
- Overdose of a drug due to a violation of the dosage regimen, accumulation or disease of the excretory organs.
- Long-term unjustified treatment.
- Abrupt (sudden) withdrawal of the drug, with exacerbation of the underlying or concomitant disease.
- Taking a medication without taking into account its interaction with other drugs used together.
- Eating disorders, unhealthy lifestyle; drug use, alcohol consumption and smoking.
Main (main) action is the pharmacological activity of a drug for which it is used in clinical practice for prophylactic or therapeutic purposes for a specific disease. For example, the main effect of Clonidine is hypotensive, Morphine is characterized by an analgesic effect, No-shpa has an antispasmodic effect. Acetylsalicylic acid, depending on the indication for use and dosage, has two main actions - anti-inflammatory and antiplatelet.
Depending on the route of administration and localization of pharmacological effects, other types of pharmacological action of drugs appear.
Resorptive action(Latin resorbere - absorption, absorption) develops after the drug is absorbed into the blood, its distribution and entry into the tissues of the body. After absorption, drugs are distributed into body tissues and interact with a molecular target (receptor, enzyme, ion channel) or other substrate. As a result of this interaction, a pharmacological effect/effects occur. This is how many medications work - “Hypnotics”, “Opioid and non-opioid analgesics”, “Antihypertensive drugs”, etc.
Local action develops when the drug comes into direct contact with body tissues, for example, skin, mucous membranes, and wound surfaces. Local action also includes the reaction of tissues (subcutaneous tissue, muscles, etc.) to the injection of drugs. Local action develops most often when using irritating, local anesthetic, astringent, cauterizing and other drugs. Have a local effect antacids- Almagel, Gaviscon forte, Maalox, which neutralize hydrochloric acid, increase the pH of the stomach and reduce the activity of pepsin. Gastroprotectors— De-nol, Venter, having a chelate effect, create a protective film on the surface of the mucous membrane and protect the inner layer of the stomach cavity from aggressive damaging factors.
Many drugs, depending on the dosage form used (tablets, capsules, dragees, solutions and suspensions for internal use) and the route of administration, have a resorptive effect, whereas when the same drug is used in another dosage form (ointment, gel, liniment, eye drops) local action occurs. For example, non-steroidal anti-inflammatory drugs: Diclofenac is available not only in tablets, solution for intramuscular administration, which cause a resorptive effect, but also for external use in the form of 1% Dicloran gel, 2% Ortofen or Diclofenac ointment, in eye drops 0. 1% solution of "Diclo-F", which has a local anti-inflammatory effect. When using suppositories under TN “Naklofen”, “Diclovit”, both local and resorptive effects occur. Another drug - "Nimesulide" - is available in the form of tablets (resorptive effect) and gel for external use under the TN "Nise" (local effect).
Irritant drugs develop effects both at the injection site and at a distance. These effects are due to reflex reactions and manifest reflex action. Sensitive nerve endings (interoreceptors) of the mucous membranes, skin and subcutaneous formations are excited, impulses along the afferent nerve fibers reach the central nervous system, excite nerve cells, and then along the efferent nerves the effect spreads to the organ/organs or the entire body. For example, when using local irritating, distracting drugs- “Mustard plasters”, “Mustard Forte” gel or “Pepper patch”, etc. The reflex action can develop at a distance from the place of initial contact of the medicinal substance with the tissues of the body, with the participation of all parts of the reflex arc. This is how ammonia vapors (ammonia 10%) act in case of fainting. When inhaled, the sensitive receptors of the nasal membrane are irritated, the excitation spreads along the centripetal nerves and is transmitted to the central nervous system, and the vasomotor and respiratory centers of the medulla oblongata are excited. Further, impulses along the centrifugal nerves reach the lungs and blood vessels, ventilation in the lungs increases, blood pressure rises and consciousness is restored. It should be remembered that large amounts of ammonia solution can cause undesirable reactions - a sharp decrease in heart contractions and respiratory arrest.
Depending on the mechanism of binding of active substances, active metabolites with receptors or other “targets”, the effect of a drug can be direct, indirect (secondary), mediated, selective (selective), preferential or non-selective (non-selective).
Direct (primary) action have drugs that directly act on receptors. For example: adrenergic agents(Adrenaline, Salbutamol) directly stimulate adrenergic receptors, antiadrenergic drugs (Propranolol, Atenolol, Doxazosin) block these receptors and prevent the action of the mediator norepinephrine and other catecholamines circulating in the blood on them. Cholinergic drugs (Pilocarpine, Aceclidine) stimulate peripheral M-cholinergic receptors in the membranes of effector cells and cause the same effects as when irritating autonomic cholinergic nerves. Anticholinergic drugs (Atropine, Pirenzepine, Buscopan) block M-cholinergic receptors and prevent the interaction of the mediator acetylcholine with them.
Indirect (secondary) action occurs when a drug, changing the functions of one organ, affects another organ. Patients suffering from heart failure often experience tissue swelling. Cardiotonic drugs, digitalis cardiac glycosides (Digoxin, Celanide) have primary effects by increasing the force of heart contractions and increasing cardiac output. By improving blood circulation in all organs and tissues, cardiac glycosides enhance the kidneys' excretion of fluid from the body, which leads to a decrease in venous stagnation and the removal of edema - these effects are secondary.
Indirect (mediated) action arises as a result of the influence of the drug on the “targets” through secondary transmitters (messengers), indirectly forming a specific pharmacological effect. For example, the sympatholytic "Reserpine" blocks the vesicular uptake of dopamine and norepinephrine. The flow of dopamine into vesicles (Latin vesicular - bubble), a morphological element of the synapse filled with a mediator, decreases. The synthesis of the neurotransmitter, norepinephrine, and its release from the presynaptic membrane are reduced. In postganglionic sympathetic nerve endings, the norepinephrine depot is depleted and the transmission of excitation from adrenergic nerves to effector cells is disrupted; there is a persistent decrease in blood pressure. Anticholinesterase agents(Neostigmine methyl sulfate, Distigmine bromide) inhibit the enzyme acetylcholinesterase, preventing the enzymatic hydrolysis of the mediator acetylcholine. Endogenous acetylcholine accumulates in cholinergic synapses, which significantly enhances and prolongs the effect of the mediator on muscarine-sensitive (M-), nicotine-sensitive (N-) cholinergic receptors.