PHARMACOLOGY (Greek pharma-kon medicine 4 logos the doctrine) — science about action on an organism of the chemical connections applied to treatment, prevention and diagnosis of diseases of the person. Studying of means for treatment and prevention of diseases of animals makes a subject veterinary F. Boley widely F. it is possible to consider as science about action of chemical connections on live organisms both animal, and vegetable i.e. as biological pharmacology. To the main sections modern F. belong pharmacokinetics (see), a pharmacodynamics (see), pharmacotherapy (see).
T. has close connection with other sciences about medicinal substances — pharmaceutical chemistry (see), a pharmacognosy ^см.), toxicology (see), etc. F. has a direct bearing on chemotherapy (see), the subject a cut makes studying of influence of chemical connections on infectious or tumoral process. T. as the biological science is connected also with other natural sciences — physiology, biochemistry, pathology, etc.
Thanks to creation of a large number of active drugs became possible to exert impact almost on all functions of an organism. In this regard the clinical medicine achieved considerable success. E.g., means for the general and local anesthesia, kurarepodobny substances promoted development of a hirugiya; discovery of new psychotropic drugs — neuroleptics, tranquilizers, antidepressants — laid the foundation for a new era in treatment of mental diseases; creation of hormonal drugs promoted
development of replacement therapy of many endocrine diseases; effective treatment of infectious diseases became possible after discovery of streptocides and antibiotics.
However, despite great achievements F., further intensive search of effective drugs is necessary for treatment of cardiovascular, psychological, oncological, viral and other diseases.
Use of pharmaceuticals has the same prescription as medicine. According to the historical periods of development of human society emergence and development F. it is necessary to consider in aspect of change of historical formations of human society.
Primitive people intuitively undertook searches in the nature of the substances alleviating suffering at diseases and injuries surrounding them. Most often for these purposes plants were used. Such therapy based on simple observations and personal experience received the name of empirical. Later, with emergence of religion use of medicinal substances gained mystical character; attendants of a cult began to be engaged in treatment of patients, and explained effect of medicinal substances with divine force.
The first attempts to systematize data on medicinal substances were made still in the ancient time. So, the Egyptian papyrus dated 16 — 17 centuries BC and found in last century G. Ebers contains data on many medicinal substances, to-rymi Egyptians, including about opium, a henbane, seeds of a castor-bean tree, nek-ry minerals used. Descriptions of medicinal substances, to-rymi used in the ancient time, are available also in other written monuments. In Hippocrates's compositions it is mentioned apprx. 300 medicinal plants. More complete description of medicinal plants was given by Teofrast (Theophrastus, 372 — 287 BC) and Diosko-rid (Dioscorides, 1 century AD). The last called the composition on this subject «Materia medica». At the beginning of a new era K. Galen for the first time developed methods of production of medicines (naira., tinctures, extracts, powders) from natural raw materials, i.e. laid the foundation of medicinal technology.
Medicinal therapy existed from an extreme antiquity also in China, Tibet, India and other countries of the East. So, in China for several centuries the treatise about roots and herbs of Shen-nuna which included the description of 365 medicinal plants was made B.C., to-ry it is possible to consider as a prototype of a modern pharmacopeia (see). References of medicinal substances contain in the Indian Veda. A large amount of medicinal substances was used in ancient Tibet. Such medicinal plants as a henbane, a nuxvomica, camphor, a licorice root, and also medicinal substances of a mineral origin were known to the Tibetan doctors: salts of iron, copper, antimony, sulfur.
During an era of feudal society the general decline of science negatively affected development of medicine in general and including development of pharmaceutical science. For a big span in the field of medicinal therapy progress was small. From documents of this time from the point of view of history of medicinal therapy Izbornik Svyatoslav» (1073) — the hand-written herbalist, the first in Russia, is of undoubted interest «. Emergence of the «Canon of medical science» made by Ibn-Sina was a big event in the history of medicinal therapy. The second and fifth books of «Canon» are devoted to the description of medicinal substances (preferential plant origin) and their use.
The alchemy which arose during an era of the Middle Ages exerted also a nek-swarm adverse impact on a condition of medicinal therapy of that time. In particular, tendencies of search of various panaceas appeared. Negative impact on development of medicinal therapy was exerted also by astrology since the effect of drugs began to be put into dependence on an arrangement of planets and constellations.
Renaissance has a positive impact on development of medicinal therapy. The founder of yatro-chemistry (see) professor Basel un-that Paracelsus entered metals and their salts unknown earlier into therapy.
Later, in 16 — 18 centuries the effective drugs of a plant origin borrowed from traditional medicine of many countries of Europe, Asia, America, napr from leaves of a foxglove, an ergot, a root of an ipecacuanha, a root of a cinchonic tree were among means of medicinal therapy.
In Russia of that time hand-written books, in to-rykh were described pharmaceuticals, hl. obr. plants, were called «herbalists» or zeleypika (see), and also «vertogradam» (from the word vertograd — a flower bed, a garden). From among such books gained the greatest fame «Cool vertograd» (1672), on the title page to-rogo it is written: «The book spoken irokh are fine and vertograd, it is chosen from many wise men about various vrachevsky things to health human at - standing». Other book of this sort is the «Composed register from dokhtursky sciences» written by the Holmogorsky archbishop Afanasy.
In 1581 under the decree of the tsar Ivan IV in Moscow the first drugstore was based, edges serviced the tsar and court. In the next years drugstores were open also in other cities of Russia. In 1581 the Pharmaceutical order was founded (see).
Peter I's reforms were of great importance for development of domestic pharmaceutical science. At it in Russia many drugstores were open, pharmaceutical industry began to arise, the basis a cut was made by the operating and created pharmaceutical kitchen gardens (see) organized in St. Petersburg on the Pharmaceutical island and in Lubnakh about Poltava. At hospitals medical schools where along with medical objects pharmaceutical business was taught were open. In 1778 in Russia the first state pharmacopeia was published. The Description of salutary plants» (1783 — 1788) made by H was the first domestic guide to pharmaceutical science «Medical veshchestvoslovy, or. M. Ambodiky-Maksimovich. More perfect guide to pharmaceutical science was written by professor of Medicochirurgical academy A. P. Nelyubin under the name «Pharmakografiya or Chemical and Medical Instruction, Preparation and Use of the Latest Drugs». It is remarkable that in the preface to this book the author wrote: «The incredible progresses made in the last decade as regards matter physicians undoubtedly should be attributed to the real condition of natural sciences and the important discoveries made in chemistry that was promoted very much by also comparative and physiological researches made by the most experienced doctors over domestic animals, and then and over people». It is undoubted that progress of chemistry and physiology at that time promoted achievements in the field of pharmacology. In 1835 the Moscow professor A. A. Iovsky wrote the textbook under the name «Tracing of the General Pharmacology».
Achievements of chemistry and physiology in 19 century were a basis for development of modern pharmacology.
At the beginning of 19 century purely vegetable alkaloids were emitted: morphine, quinine, strychnine, caffeine, atropine, etc. To number of the opening and chemistry of that time which exerted huge impact on development F., it is necessary to refer synthesis of urea — • the first organic matter, carried out in 1828 by F. Voeller, the synthesis of aniline from nitrobenzene developed by H. N. Zinin, and laid the foundation for synthesis of new dyes and pharmaceuticals, creation of the theory of a structure of chemical substances by A. M. Butlerov. Due to the progress of the general chemistry the pharmaceutical chemistry arose (see) and chemical pharmaceutical industry began to develop (see). In the middle of 19 century in practical surgery the first synthetic means for the general anesthesia were used: diethyl ether [Long (Page W. Long), U. Morton, N. I. Pirogov] and chloroform (J. Simpson).
Physiological researches of K. Bernard, Ch. Bella, F. Maj-ndi, I. Müller, I. M. Sechenov, V. Ya. Danilevsky made possible studying of effect of medicines in experimental conditions that promoted knowledge of mechanisms of their action. In 1847 Bukhgeym created at department of pharmacology of Derptsky (nowadays Tartu) un-that the first laboratory of experimental pharmacology. Later experimental F. began to develop successfully in Moscow un-those thanks to A. A. Sokolovsky's works. Two managements were written to them: «Course of an organic
pharmacodynamics» (1869) and «Inorganic pharmacology» (1871). In Kiev un-those V. I. Dybkovsky conducted a series of researches on experimental studying of cardiovascular means. It made a course of lectures on pharmacology (1871). Bright representative experimental F. the end 19 and the beginnings of 20 centuries was O. Shmideberg.
To a recent trend in F. — — P. Ehrlich who received salvarsan and proved a possibility of selective effect of drugs on microorganisms in the conditions of a macroorganism laid for chemotherapy the foundation (see Chemotherapy). In the 30th 20 century G. Domagk found antibacterial properties of sulfanamide connections. In 1929 penicillin was discovered by A. Fleming, to-ry in 1940 G. Florey and Cheyn (E. V. of Chain), and in 1942 — 3 received in pure form. V. Ermolyeva and T. I. Balezin.
A little later chemotherapy inf. diseases the chemotherapy of malignant tumors began to develop (see Chemotherapy of tumors). Nitrogenous iprita were the first antineoplastic means. Afterwards the considerable number of antineoplastic means was received (see). The big role in development of chemotherapy of tumors was played by L. F. Larionov's researches.
The present stage in development domestic experimental F. it is connected with I. P. Pavlov and N. P. Kravkov's works. The discoveries made by I. P. Pavlov in the field of physiology of cardiovascular system, digestion and nervous activity substantially promoted progress in studying of the mechanism of action of many pharmakol. substances. I. P. Pavlov's school left prominent pharmacologists: V. V. Savich, N. A. Soshestvensky, I. S. Tsitovich. N. P. Kravkov headed department of pharmacology of Army medical college in 1899 (after I. P. Pavlov) and 25 years directed this department, having created big school of pharmacologists (S. V. Anichkov, V. I. Berezin, M. I. Gramenitsky, V. V. Zakusov Sr., V. V. Zakusov Jr., A. I. Kuznetsov, M. P. Nikolaev). It and his employees conducted numerous basic researches in different areas experimental F.
To development domestic F. actively N. P. Kravkov's contemporaries A. A. Likhachev,
V. I. Skvortsov, and also N. V. Vershininsistematicheski studying medicines of a plant origin promoted. Many achievements in biological standardization of medicines domestic F. it is obliged to K. D. Sargin. A. I. Cherkes directing within 28 years department of pharmacology Kiev medical in-that was a prominent pharmacologist.
One of founders of domestic industrial toxicology N. V. Lazarev made a contribution to development F. and toxicology the theoretical researches about communication between physical. - chemical properties of substances and their biological activity.
From foreign scientists a big contribution in modern F. O. Levi, G. Dale, A. J. Clark, J. H. Gaddum, the Item Trende-lenburg, V. Shtraub, K. Geymans, D. Bowe, K. Schmidt, etc. brought.
Before Great October socialist revolution in Russia there were no special research in-t dealing with problems of pharmacology. In 1920 in Moscow the All-Union research chemical and pharmaceutical institute (In NIH FI) which later opened branches in Sverdlovsk and Kupavna was founded. Similar institutes were created in Kharkiv, Tbilisi and Novokuznetsk. In 1931 for studying of officinal flora it was organized All-Union! institute of medicinal and aromatic plants (VILAR, nowadays VILR) with numerous zone experimental stations.
In 1952 in Moscow the Institute of pharmacology of the USSR Academy of Medical Sciences was founded. Almost were at the same time created Institute of organic synthesis of AN of the Latvian SSR in Riga and Institute of thin organic chemistry of AN of the Armenian Soviet Socialist Republic in Yerevan where researches on research and studying of new pharmaceuticals are conducted. In the 70th in Moscow the Institute on biological tests of chemical compounds was organized. Besides, in Leningrad at Institute of experimental medicine there is a big department of pharmacology. Due to growth of medical and pharmaceutical schools the number of departments of pharmacology considerably increased, on to-rykh researches in the field of theoretical and applied pharmacology are carried out.
Abroad intensive researches on F. are carried out in pharmakol. laboratories of various universities, chemical and pharmaceutical firms, research in-comrades.
Specialists pharmacologists in the USSR are united in All-Union scientific in pharmacologists, a cut was founded in 1960. Before the Soviet pharmacologists were a part All-Union scientific about-va biochemists and pharmacologists, at Krom in 1937 the section of pharmacologists and toxicologists was organized. The special scientific magazine «Pharmacology and Toxicology» is the same year founded.
Teaching pharmacology in the USSR at medical institutes is conducted during two semester on younger courses. It includes lectures and laboratory researches on experimental F., and on the 6th course classes are given and lectures on clinical pharmacology are given. In pharmaceutical and veterinary in-ta, on pharmaceutical f-takh of medical higher education institutions, and also in average medical, veterinary and pharmaceutical schools teaching F. it is conducted according to special programs.
According to contents F. it is accepted to divide into the general and private. Problem of the general F. studying of the main patterns of action of chemical connections on live organisms, and also clarification of the mechanism of this action is. Tasks private F. studying of a chemical structure is, physical. - chemical properties, pharmacokinetics (see), pharmacodynamics (see) and pharmakoterapevtichesky use of separate pharmaceuticals (see Pharmacotherapy).
Pharmaceuticals enter into an organism in the different ways: through a mouth, subcutaneously, it is intramusculary, intravenously, inhalation, etc. Speed of approach of effect first of all depends on a way of administration of medicine.
After absorption of pharmaceuticals in blood there is their distribution in fabrics. As a rule, they are distributed in an organism unevenly that in considerable a stenena depends on intensity of blood circulation in bodies.
of pharmaceuticals in an organism undergoes chemical transformations and only the few them them are allocated in not changed look. Metabolism of pharmaceuticals can be carried out by oxidation, recovery, hydrolysis and conjugation (alkylation, acetylation, interaction with glucuronic to - that). Very great influence on process of biotransformation is exerted by enzymes. Especially intensively metabolism of pharmaceuticals happens in a liver. As a result of biotransformation of an obrmore polar compounds, i.e. more water soluble zutsya, to-rye are easier brought out of an organism. As a rule, the majority of pharmaceuticals in the course of biotransformation lose physiological activity, but in some cases their metabolism in an organism leads to formation of connections with bigger physiological activity. Elimination of pharmaceuticals or products of their metabolism happens through kidneys, intestines, lungs, skin, mammary glands.
Processes of absorption, distribution, metabolism, removal make a subject of pharmacokinetics (see). The modern equipment allows to define with high precision in an organism very trace amounts pharmakol. substances and the changes happening to them. Carry out quantification of samples of blood, urine, expired air, biopsy material, etc. The data obtained in such way subject to mathematical processing for creation of the theoretical models allowing to interpret objectively the biological phenomena. The concept about a so-called lump-partmentakh forms a methodical basis of it (cameras), i.e. bodies, fabrics and excretes of an organism where there are specified processes.
From problems of the general pharmacology paramount value has dependence biol. activities of substances from their chemical structure and physical. - chemical properties. Very often the substances similar on a chemical structure (e.g., sex hormones), have unequal effect on an organism, and the substances possessing various chemical structure cause identical pharmakol. effects (e.g., anesthetics). During the studying of dependence biol.
activity of substances from their chemical structure needs to consider stereospecificity of molecules, their conformational properties, interatomic distances, electronic orbits, a complement a rnost to biol. to substrates. From physical. - chemical properties biol. active agents the greatest value has water solubility, lipids, extent of ionization, a volatility.
The problem of effect of medicines on receptor educations (see Receptors, cellular receptors) is of great interest since development pharmakol begins with it. effect. Ability of biologically active agents to connect to a receptor (affinity) is designated by the term «affinity». For an agonist this size is expressed by its concentration, at a cut is observed defined pharmakol. effect. A numerical indicator of affinity of an agonist is the negative logarithm of its molar concentration, at a cut quantitatively certain effect develops. The affinity of the antagonist to a receptor is expressed by its molar concentration, at a cut it is necessary to double molar concentration of an agonist to gain the same effect. A numerical indicator of affinity is the negative logarithm of molar concentration of the antagonist, at a cut it is necessary to double molar concentration of an agonist to gain effect, usual for it. This size is designated as ra2. It is a measure of competitive antagonism of medicinal substances (see).
Unlike competitive antagonism, to-ry always happens bilateral, there is still a so-called nonspecific antagonism of pharmaceuticals when in the presence of the antagonist it is not possible to gain usual maximum effect, despite strengthening of an agonist, i.e. between an agonist and the antagonist there are no competitive relations. Such antagonism is referred to allosteric or allokhroyny effects. An indicator of nonspecific antagonism is relative reduction of the maximum effect caused by an agonist in the presence of the antagonist in comparison with the maximum effect arising at action of high concentration of an agonist. Activity of the nonspecific antagonist is determined by its molar concentration, at a cut the maximum effect caused by an agonist decreases twice. The negative logarithm of this concentration is taken for a measure of nonspecific antagonism and designated as pD2.
The maximum effect, to-ry causes a standard agonist (i.e. when it is supposed that all receptors are occupied), reflects its efficiency, or the «internal activity» (intrinsic activity) designated by an and symbol and taken as a unit (and = 1), and internal activity of other agonists conceding on activity to standard substance express as fraction: and = 0,9; and = 0,8 etc.
The incentives arising in cellular receptors i.e. in points of linkng of pharmaceuticals with external and inner cellular membranes or enzymes, are exposed to transformation, strengthening, modulation therefore the subsequent incentives causing development pharmakol form. effect.
Clarification of the mechanism of effect of medicines is one of urgent and difficult problems of pharmacology. Only for nek-ry substances philosophy of action on an organism are established. So, it is known that physostigmine, prozerin or organophosphorous connections inactivate acetylcholinesterase; Sydnocarbum activates adenylatecyclase; caffeine inhibits phosphodiesterase; compounds of arsenic, antimony and heavy metals (mercury, etc.) affect thiol enzymes. It is established that Phenaminum detains the return capture of noradrenaline in the corresponding synapses. An important factor in the mechanism of effect of neurotropic substances are changes in synoptic transfer of nervous impulses that affects integrative function of a nervous system. It is possible to take for granted influence of cardiac glycosides on sokratitelny properties of cardiomyocytes. There are substances influencing an organism through closed glands. Thus, many substances exert impact on biochemical processes in an organism. At the same time the pharmaceuticals causing in an organism of change of a biophysical order, in particular, the adsorptions influencing processes, diffusions, osmosis on aggregate state of molecules are known. Therefore, mechanisms of effect of medicines can be considered in different aspects: molecular, cellular, organ and system.
Development pharmakol. effect considerably depends on a dose (see) drug. Knowledge of this dependence for each drug allows to dose it correctly. Methods of mathematical statistics allow to express this dependence in very exact sizes: ED16, ed5, „ed86, LD50, i.e. by simple calculations establish the effective dose (ED), at a cut the set effect in an experiment respectively at 16%, 50%, 86% of animals or deadly effect at 50% of animals (see P r it is upholstered - a method) is observed.
Pharmakol. action is taken to classify as local and the general, or resorptive; direct and indirect, a cut can be reflex; reversible and irreversible. Effect of medicine can be to some extent selective, or specific when it is limited to separate cells or bodies.
Nek-ry pharmaceuticals along with desirable therapeutic effect cause side effect (see. Side effects of pharmaceuticals). Naira., if morphine is applied as an analgetic, then the obstipation or respiratory depression accompanying analgetic effect consider as side effect. However at diarrhea or heavy short wind these effects are considered as main.
Quite often pharmaceuticals cause a sensitization of an organism and allergic reactions in individuals that can lead to development of a medicinal allergy (see). Less often at nek-ry persons the inborn intolerance of medicine is observed (see the Idiosyncrasy).
It is necessary to consider that at repeated administrations of medicines their action can amplify. It depends on their accumulation in an organism, i.e. on material cumulation, or on summing of separate effects of their action, i.e. on functional cumulation (see Cumulation). In nek-ry cases at repeated administrations of medicines their action can be weakened, i.e. there occurs accustoming (see Accustoming to pharmaceuticals). Special type of accustoming is the tachyphylaxis (see), i.e. sharp easing of effect at administration of drug through small time slices (minutes), napr, ephedrine.
Nek-ry pharmaceuticals at repeated receptions cause so-called medicinal dependence (see). The termination of administration of drug at medicinal dependence is followed by heavy disorders of many mental and somatic functions, i.e. the phenomena of abstinence (abstention).
Often apply to achievement of the best therapeutic effect not one, but two or bigger number of drugs. At the same time their action can amplify (synergism) or be weakened (antagonism). If effects of separate pharmaceuticals are summed up, then call such phenomenon the additive action, napr, at a combination of diethyl ether to nitrous oxide and if cumulative effect exceeds the sum of effects of formulation components, then such phenomenon is called potentiation, napr, at a combination of anesthetics to neuroleptics (see the Synergism of medicinal substances). Synergism as well as antagonism can be direct if target organs same, or indirect if target organs different. The antagonism based not on physiological influence, and on chemical or physical and chemical neutralization of the applied means call An-tidotizmom.
For the correct assessment of effect of the combined action it is necessary to use the principle of the graphic analysis developed by O. Levi. First, it is necessary to define dependence of effect of a dose of each formulation component, i.e. to construct the corresponding bologramma. Secondly, to construct an izobola of mix, i.e. the line on ordinate axis connecting points of identical effect of medicines. For final assessment of effect of the combined action it is necessary to compare the izobola of mix received experimentally, with izoboly, received by addition bologramm for each formulation component.
Development pharmakol. effect substantially depends on many, in particular genetic properties of an organism and it fiziol. states. Studying of their role in reaction of an organism to pharmaceuticals makes a subject of special area F. — pharmacogenetics (see) besides, matter age, sex, weight (weight) of a body, character of food, a kind of activity, patol. states.
The standard system of classification of pharmaceuticals does not exist and they can be systematized by different criteria: 1) on action on physiological systems of an organism; 2) on a wedge, to use; 3) on a chemical structure. However often use the mixed classification since each of the specified signs separately does not give a total characteristic of pharmaceuticals (see).
Research new pharmakol. means it can be carried out in the different directions. Due to the progress of synthetic chemistry became possible to receive biologically active agents identical or close on a chemical structure to the substances of a natural origin which are taking part in regulation of physiological functions. This tendency gained the dominating value in the directed search of new pharmaceuticals. In a crust, time preference is often given to hormones, enzymes, metabolites, neurotransmitters, neuropeptids, their analogs and homologs, many from to-rykh are endogenous ligands of the corresponding receptors. At the directed synthesis of new medicinal substances the important place is taken by search of exogenous ligands of certain receptors.
Studying of pharmaceuticals consists of two stages: preclinical and clinical. The first of them is only and irreplaceable for assessment of safety of use of medicine in medical practice. Preclinical studying of pharmaceuticals is carried out in experimental conditions on animals.
First problem of preclinical studying pharmakol. substances clarification of a range of physiological activity is. The obligatory program of preclinical studying includes researches on a pharmacodynamics and the mechanism of action with use of physiological, biochemical, biophysical, morphological methods, and also on pharmacokinetics. It is necessary to define precisely toxicity of drug in acute and hron. animal experiments of different types. Besides, conduct special researches regarding detection of embriotoxity, teratogenecity, a mutagenicity, oncogenicity. During the conducting pilot studies consider breed, purity of the line of animals, their age, sex, detention regime, quality of food, time of carrying out observations. During the planning of pilot studies it is especially important to use adequate methods and to consider experimental conditions, in particular, ways of anesthesia, immobilization. Check of efficiency of pharmaceuticals on pilot models of the morbid conditions having looking alike diseases of the person is desirable.
Tsri positive takes of pilot study of drug (safety of use and potential efficiency) after obtaining special permission of Pharmacological Committee M3 of the USSR is passed to its clinical studying (see Pharmacology clinical). For objective assessment of pharmaceuticals in clinic it is necessary to provide the correct selection of the contingent of patients (in nosological forms, age, sex and other signs); the sufficient number of the persons which are under observation, and use of methods of mathematical statistics for establishment of the importance of the received results. For objectification of the obtained data use placebo (see) and a double blind method, and also carry out approbation of new drugs to several to lay down. institutions. The most close check behind implementation and production of new medicines is necessary. And abroad use various control systems of pharmaceuticals to these purposes in the USSR (see).
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V. V. Zakusov.