pharmakon medicine + dynamikos strong) — the component of pharmacology studying localization, the mechanism of action and pharmacological effects of medicinal substances.
Influence of medicinal substances on functions of any body or fabric is caused by direct or indirect impact of substances on biochemical substrates, from to-rykh this or that function depends. Direct interaction with substrate is most often carried out by compound of medicinal substance with specific receptors, to-rymi there can be any functionally significant macromolecules or their fragments. Except specific receptors, allocate so-called nonspecific receptors, during the binding with to-rymi medicinal substances do not cause functional changes.
The majority of the known types of specific receptors belongs to the cellular proteins localized or in a cellular membrane (holinoretseptor, insulin receptors, etc.), or in cytoplasm (receptors of the majority of steroid hormones). Specific receptors and other chemical nature, napr, nuclear nucleinic to - you are known, with to-rymi antineoplastic means (see) from among the alkylating substances interact. Receptors of enzymes (see), napr, active centers of acetylcholinesterase, monoamine oxidase, etc., are also considered as specific receptors. Nek-ry specific receptors, in particular N-holinore-tseptory of skeletal muscles, are allocated in the isolated look and their detailed structure is established. Isolation of the majority of other specific receptors meets great methodical difficulties. Character of many specific receptors is not established though their existence is proved by different methodical receptions of willows of t. h by radioli-gandny methods (see Radioizo-topnoye a research).
Specific receptors have a certain localization. E.g., m-holinoretseptory are localized in postsynaptic membranes of effector cells in the field of the terminations of cholinergic fibers (see
the Synapse); opiate receptors in c. N of page (see Opiates endogenous) are in neurons of gray matter of okolovodoprovodny space and back horns of a spinal cord.
Compound of medicinal substances with specific receptors can be carried out due to various chemical bonds having unequal durability. So, approximate anchoring strength of kurarepo-dobny substances (see) with holinoretsep-Torahs for electrostatic (ionic) interaction makes 5 kcal/mol, ion-dipole — 2 — 5 kcal/mol, a dipole - dipolar —
1 — 3 kcal/mol, hydrogen bindings
of 2 — 5 kcal/mol, van-der-vaalsovykh
of bonds — 0,5 kcal/mol, hydrophobic bonds — 0,7 kcal on one CH2-group-pu. Reduction of anchoring strength depending on distance between atoms for electrostatic interaction makes-2, ion-dipole —-3, a dipole - dipolar —-4, hydrogen bindings —-4, van-der-vaalsovykh of bonds — "7. Such bonds can be broken that provides reversibility of effect of medicinal substances. Stronger are covalent bonds, to-rye provide long and often irreversible effect of substances (e.g., the alkylating antineoplastic means). The majority of medicinal substances connects to receptors reversibly. At the same time, as a rule, the nature of connection is very difficult:
can participate in it at the same time ionic, a dipole - dipolar, van-der-vaalsovye, hydrophobic and other types of communication that in many respects is defined by a complementarity of substance and a receptor and respectively extent of their rapprochement among themselves.
Durability of linkng of substance with receptors is designated the term «affinity». The substances operating on the same receptors can possess in relation to them different degree of affinity. At the same time substances with higher affinity can force out substances with smaller affinity from connection with receptors. For definition of an equilibrium state between the «occupied» receptors (DR), free receptors (R) and free substance (D) the dissociation constant is used (To D), to-ruyu determine by the following formula: [D] x [R]
of Kd ~ w •
A negative logarithm of KD (pKD) is an indicator of affinity. For the characteristic of affinity often use an indicator of pD2, i.e. a negative logarithm of EC50 (concentration of substance, in a cut it causes the effect making 50% of the maximum effect).
To cause ability of substances after their interaction with specific receptors biochemical or fiziol. the reactions corresponding to the functional importance of these receptors are called internal activity. Internal activity of any substance is defined by the attitude of size of its maximum effect towards the maximum effect of other (standard) substance. So, if to take internal activity of substance A for unit, and the maximum effect of substance B makes 50% of the maximum effect of substance A, then internal activity of substance B will make 0,5. It should be noted that the maximum effect of substance can be reached at «occupation» by this substance only of a part of specific receptors.
The substances having affinity and internal activity are called agonists. At the same time substances with the expressed internal activity call full agonists, and the substances combining properties of an agonist and the antagonist — partial (partial) agonists. The substances having affinity and not having internal activity, but capable to interfere with action of agonists, call antagonists. Partial agonists can be antagonists of full agonists also. E.g., a partial agonist of opiate receptors Nalorfinum (see) works to similarly full agonist of these receptors to morphine (see), though is weaker than the last. At the same time at their combined use Nalorfinum weakens or eliminates effects of morphine; in particular, the oppressing effect of morphine on breath is eliminated.
Specific receptors can have the same or different places of binding for agonists and antagonists. Different places of binding for different agonists are possible. In that case when an agonist and the antagonist have the same places of binding, and the blocking action of the antagonist on a receptor completely is eliminated during the strengthening of an agonist (the maximum effect of an agonist is reached), the relations between the antagonist and an agonist designate as competitive antagonism (see Antagonism of medicinal substances). If places of binding for an agonist and the antagonist are various, then the relations between them define as non-competitive antagonism. For the characteristic of antagonists often use an indicator ra2 (a negative logarithm of molar concentration of the antagonist, at a cut for obtaining standard effect of an agonist it is necessary to double its concentration).
In the conditions of the whole organism agonists and antagonists cause changes of these or those fiziol. functions. Action of antagonists at the same time is defined by the fact that they interfere with influence on specific receptors of the corresponding natural ligands (e.g., the antagonist of m-holinoretseptorov atropine interferes with action of their agonist of acetylcholine). Changes, to-rye are directly connected with interaction of substances with specific receptors, designate the term «primary pharma to logical reaction», edges can be the beginning of the whole series of the reactions leading to stimulation or oppression defined fiziol. functions.
The changes of functions of bodies or systems (e.g., changes of force and heart rate, a tone of unstriated muscles of internals, secretions of glands, the ABP, etc.) caused by medicinal substance designate as pharmacological effects of this substance. So, for cardiac glycosides (see) primary pharmakol. reaction is oppression of activity of transport Na+, K-ATP-ases of fibers of a myocardium, edges is regarded as a possible specific receptor for cardiac glycosides. In this regard receipt of K+ in muscle fibers and escaping of Na fibers + is broken, contents Sa2 + in cytoplasm increases that promotes interaction of actin and a myosin. Increase in force of cordial reductions is result of the specified changes that is the basic pharmakol. effect of cardiac glycosides.
Long impact of agonists on specific receptors quite often is followed them-sensitizatsiyey (decrease in sensitivity). The last can be connected with changes of receptors, reduction of their quantity (density) or disturbance of processes, to-rye follow excitement of receptors. At the same time pharmacological effects of agonists become less expressed.
Thus, pharmacological effects of the majority of pharmaceuticals are connected with their impact on the corresponding specific receptors. At the same time effect of nek-ry medicinal substances is not connected with specific receptors. So, for osmotic diuretics — the mannitol, urea (see Diuretics) — does not exist specific receptors. These substances increase osmotic pressure (see) in renal tubules owing to what the reabsorption of water is broken and the diuresis increases. Action of the adsorbing means (see), acid-forming diuretics, complexons is not connected with specific receptors (see).
Ways, to-rymi medicinal substances cause these or those pharmakol. effects, designate the term «mechanisms of action». This concept is used for an explanation of effect of medicinal substances at the molecular, organ and system levels. E.g., the mechanism of action of antikholinesterazny means (see) at molecular level comes down to blockade of acetylcholinesterase by interaction with its anion and esterazny the centers. At the same time, explaining the mechanism of hypotensive action of antikholinesterazny means, specify bradycardia and vasodilatation as the reason of this effect, i.e. consider the mechanism of this effect at the organ level.
Mechanisms of effect of separate medicines are studied in different degree. In this regard researches of mechanisms of effect of medicinal substances are conducted constantly, and ideas of the mechanism of effect of this or that medicinal substance in process of obtaining new data can not only become more detailed, but also it is essential to change.
Subject F. also types of effect of medicines are. Distinguish a local, resorptive and reflex effect, the main and side, direct and indirect, reversible and irreversible, selective and not selective, therapeutic and toxic effect. Effect of local anesthetics at surface anesthesia though at the same time a part of anesthetic can be soaked up and have resorptive effect, i.e. a systemic effect after absorption can be an example of local action. Reflex the irritating substances work, e.g., (see).
Main (basic) call effect of substances, a cut it is used in the medical purposes in each case (in other cases it can be collateral). The action which does not have medical value in any specific case call collateral. Side effect is, as a rule, adverse for the patient (see. Side effects of pharmaceuticals).
Effect of cardiac glycosides on heart can be an example of direct action. Indirect iu. action is shown, in particular, by the increase in a diuresis connected with improvement of blood supply of kidneys.
of pharmaceuticals works reversibly, however also irreversible action, napr, blockade of acetylcholinesterase organophosphorous connections is possible (see).
Pharmaceuticals change various functions of an organism with different degree of selectivity of action. An example of selective effect is the mioparaliti-chesky effect of nek-ry kurarepo-dobny means, to-rye in therapeutic doses influence other fabrics and bodies a little. Quite often instead of the term «selective effect» use the term «preferential action» since true selectivity of effect of medicinal substances practically does not meet. A number of medicinal substances exerts impact at the same time on many functions of an organism, i.e. shows not selective effect. Anesthetics belong to such substances, e.g., (see the Anaesthesia, t. 20, additional materials).
Effect of substances at exceeding of their therapeutic doses call toxic. Adverse effects of the medicinal substances applied by women during pregnancy concerning a fruit designate as embriotoksichesky action. If such action leads to inborn malformations (see), then it is designated as teratogenic effect (see the Teratogenesis). Embrio-toksichesky, and including teratogenic, effects usually consider as manifestation of side effect of medicinal substances.
T. medicinal substances depends on many factors, in particular on properties of substances, their dosage, time of their appointment, a combination with other medicines, and also on features of an organism, on to-ry these substances influence.
The most important factor defining effect of medicinal substances is their chemical structure. In general similar features of F. Odnako in some cases F also are characteristic of substances with a similar chemical structure. substances with very close chemical structure can significantly differ. Significant differences in size pharmakol can be an example. effects between stereoisomers of a number of pharmaceuticals (adrenaline, an anaprilin, etc.). A certain value for F. pharmaceuticals can have both their physical and physical. - chemical properties: water solubility and lipids, volatility, extent of dissociation, etc.
Effect of medicines substantially depends on their dose (see) or concentration. In general at increase in a dose also expressiveness pharmakol increases. effects of pharmaceuticals. Most often at the same time S-shaped dependence between a dose and size of effect is registered; also linear and hyperbolic dependences are possible. By comparison of activity of two pharmaceuticals compare their isoeffective doses, usually doses of 50% of effect (ED50). It is considered that substance A is so many times more active than substance B, in how many ED50 of substance A of less ED50 of substance B. Besides, allocate the concept «efficiency» of substances. About efficiency judge by the size of the maximum effect of medicine.
Dependence of effect of medicinal substances on time of their appointment belongs to the section of a hronofarmakologiya. Day-night rhythms in operation of pharmaceuticals are most in detail studied, to-rye depend on a tsirkadnost of the processes happening in an organism (in particular, circadian rhythms in secretion of hormones are known, to activity a microsome of lny enzymes, etc.). So, glucocorticoid drugs (see Glyukokor tikoidny hormones) are most effective at their appointment at 8 o'clock, insulin (see) — at 8 — 13 o'clock, allergic reactions to medicinal substances arise more often at 21 — 24 o'clock (in the same time of day antihistaminic means are most effective). Also year rhythms pharmakol are known. activities; assume existence of monthly and week rhythms.
T. pharmaceuticals can change at their repeated appointments. So, development of accustoming to pharmaceuticals is possible (see). At the same time for achievement of former effect it is necessary to increase a dose of medicinal substance. Bystry development of accustoming is designated the term a tachyphylaxis (see). At repeated administrations of medicines to them medicinal dependence can develop (see).
At co-administration of two pharmaceuticals they can strengthen (synergism) or weaken action of each other (antagonism). Distinguish the following types of a synergism: potentiation, the additive action, a direct synergism, an indirect synergism (see the Synergism of medicinal substances). Antagonism can also be direct and indirect. The antagonism connected with chemical or physical. - chemical interaction of medicinal substances, call an antidotizm.
On F. medicinal substances can exert impact a sex, age, functional and patol. states, and also genetic features of an organism. So, it is known that activity a microsome of lny enzymes of a liver, to-rye is inactivated by many pharmaceuticals, it is stimulated with androgens therefore men are steadier against toxic effect of substances in comparison with women. System of microsomal enzymes very much nesothe vershenna at newborns and substantially loses the activity at advanced age, than higher sensitivity of children and elderly persons to a nek-eye to pharmaceuticals speaks. The medicinal substances stimulating any functions (stimulators of c. N of page, hormonal drugs, etc.) are, as a rule, more effective against the background of oppression of the corresponding functions. Nek-ry substances have therapeutic effect only in the conditions of pathology, napr, antipyretics (see), antidepressants (see) etc.
Explain with the genetic features (which are genetically caused by enzymopathies) an idiosyncrasy (see), i.e. unusual reactions to separate medicines. Considerable lengthening of action of Dithylinum (insufficiency of pseudo-cholinesterase), hemolysis at use the prima cinchona (insufficiency glyukozo-6-phosphate — dehydrogenases), etc.
Krom of the listed factors, T can be an example of an idiosyncrasy. it is closely connected with pharmacokinetic features of pharmaceuticals, i.e. their distribution, deposition, the nature of metabolism and removal from an organism (see Pharmacokinetics).
Bibliography: X and r to e in and the p D. A. Pharmakologiya, M., 1980; With s a k at T.
Z. Introduction to general pharmacology, p. 13, N. Y., 1979; The pharmacological basis of therapeutics, ed. by A.
Gilman a. o., p. 28, N. Y., 1980. V. V. Maysky.