CHOLINOMIMETIC SUBSTANCES (sincaline + the Greek mimetikos able to imitate, reproducing; synonym: holinopozitivny substances, cholinomimetics) — substances, action to-rykh are reproduced by effect of excitement of cholinergic nerves or a mediator of acetylcholine.
According to an orientation of action on m - and N-holinoretseptory (see the Autonomic nervous system, physiology) X. divide into 3 groups century: m - cholinomimetic substances (m cholinomimetics) — muscarine (see), Pilocarpinum (see), aceclidine (see), arecoline and oksotremorin; N-care-nomimeticheskiye for substances (N-holino-mimetiki) — nicotine (see), lobeline (see), cytisine (see Cytitonum), tetramethyl-ammonium, anabasine (ShM. Pesticides, table) and Subecholinum (see); m - and N - cholinomimetic substances (m - and N cholinomimetics) — acetylcholine (see) and Carbacholinum (see).
On a chemical structure of X. are quarternary century (acetylcholine, Carbacholinum, muscarine, Subecholinum, tetramethyl ammonium) or tertiary (arecoline, aceclidine, Pilocarpinum, etc.) ammonium connections. X. century, the representing quaternary ammonium compounds, badly get through a blood-brain barrier (see) owing to low lipophilicity and in this regard have selective effect on peripheral holinoretsepto-ra. X. century from among basic nitriles, on the contrary, differ in high lipophilicity, well get into c. N of page and therefore exert the stimulating impact not only on peripheral, but also on the central holinoretseptor. In this regard X. it is possible to divide into two groups century: X. century of selective peripheral effect (quaternary amkhmoniyevy compounds) and X. century of the central and peripheral action (tertiary ammonium connections).
On character pharmakol. actions of X. are close to anti-cholinesterases-nym to means century (see). However unlike antikholinesterazny means, to-rye prolong effects of endogenous acetylcholine, X. affect directly holinoretseptor century and cause strengthening of efferent influences of the autonomic nervous system on internals, glands, vessels, including vessels of skin and mucous membranes (see the Autonomic nervous system, the table).
m-Holinomimetiki cause excitement of parasympathetic department of the autonomic nervous system that is shown by a miosis, bradycardia, increase in a tone of unstriated muscles of internals, hypotension, etc. n-Holinomimetiki exert the stimulating impact on sympathetic a ganglion, chemoceptors of a sinocarotid zone, chromaffin cells of adrenal glands and neuromuscular transmission. In this regard separate effects of N-ho-linomimetikov not only do not match effects of m-holinomimeti-kov, but also can be opposite. So, m cholinomimetics cause decrease in the ABP, and N cholinomimetics raise it that is caused by excitement sympathetic gangliyev and release of adrenaline from chromaffin cells of marrow of adrenal glands. Two-phase action is characteristic of N cholinomimetics: after excitement there comes blockade of N-holino-receptors. The paralyzing action prevails at use of N-ho-linomimetikov in high doses.
At introduction of m - and N-holinomime-tics hl are observed. obr. signs of excitement a m-holinoretsepto-ditch, to-rye mask the effects connected with stimulation of N-holino of receptors. Action of m - and N-holinomi-metikov on N-holinoretseptory fully comes to light only in the conditions of preliminary blockade of m-holino of receptors atropine
(see) or other m-cholineregional eyes-Torahs (see. Cholinolytic substances).
At the heart of the mechanism of action of X. century their structural looking alike acetylcholine providing ste-richesky (space) compliance of a molecule X lies. century to an arrangement of the functional centers of holinoretseptor. At the maximum preservation of such compliance (proximity of structure, the general dimensions of a molecule, a relative positioning of active centers) X. imitate effects of acetylcholine century, i.e. have effect both on m - and on N-holinoretseptory. The listed features Carbacholinum, on structure close to acetylcholine and differing from the last only in existence of an amino group in an acid part of a molecule instead of methyl group has.
At interaction of X. century with care-noretseptorom there is a change of its conformation and increase in permeability of a subsynaptic membrane for ions. Depolarization of a subsynaptic membrane is caused and there is an action potential.
Selectivity of action of X. century from among quaternary ammonium compounds on m-ho of l of Eno receptors it is reached by introduction to a molecule of these connections of the additional active group corresponding on an arrangement to ketonic oxygen of acetylcholine and a branch of carbon in ^-situation concerning a nitrogen atom. By such way selectively operating m cholinomimetics mekholin and betanekhol, being respectively analogs of acetylcholine and Carbacholinum were received. It is also established that m - cholinomimetic action possess only laevoisomers of a mekholin and muscarine that testifies to stereospecificity of action of X. century Stereospetsifichnost depending on an optical isomerism (see) is inherent as well to N cholinomimetics. However at them it is expressed in much smaller degree. Possibly, it is connected with the fact that not three active centers as it takes place at m-ho-linomimetikov, and two take part in implementation of interaction of cholinomimetic substances with N-holino a receptor. Thus, N-holinoretseptor less ste-reospetsifichen. Also the fact that for action on m-holinoretseptory molecular asymmetry of cholinomimetic substance has bigger value, than for action on N-holinoretsep-Torahs demonstrates to it.
Alkaloids Pilocarpinum and arecoline, and also synthetic drugs oksotremorin and aceclidine belong to m cholinomimetics from among tertiary ammonium connections. Despite the lack of close structural looking alike acetylcholine, at these connections kept distances, necessary for a holinomimeta of chesky action, between a nitrogen atom and two active centers»
to Protozoa on a chemical structure of N cholinomimetic from group a chetver of tichny ammonium connections yav tetramethyl ammonium lyatsya. Its molecule represents as if separate cationic «head» of acetylcholine. At increase in dimensions of a molecule the tetrametilammo-niya can be reached strengthening of activity. 1,1-dimethyl-4-fenilpiperazin (DMFP) was so received. On chemical structure it can be presented as tetramethyl-ammonium, two methyl radicals at to-rogo are closed in a ring by accession phenyl a diethyl and a mine. DMFP is applied in experimental pharmacology as strong a feather of ferichesky N cholinomimetic. Increase in N - cholinomimetic activity is reached also by a doubling of a molecule of acetylcholine as it takes place at Subecholinum.
Alkaloids nicotine, anabasine and coniine concern to N ~ to cholinomimetics from among basic nitriles. Structures of the first two can be presented as pair combinations of Goethe of rotsiklichesky rings — pyridine and piperidine (anabasine) or pyridine and pyrrolidine (nicotine). In coniine one of rings is replaced by the propyl radical. Due to the high toxicity these alkaloids in to lay down. the purposes are not applied. They are used by hl. obr. in experimental pharmacology. Also lobelias and cytisine belong to derivatives of piperidine. Excitement of chemoceptors of a sinocarotid zone is prevailing in operation these drugs (see. Reflexogenic zones).
n-Holinomimetiki from group of basic nitriles well get through a blood-brain barrier and exert the expressed impact on c. N of page (cause reaction of activation to EEG, stimulate higher nervous activity, strengthen release of posterior pituitary hormones). In high doses they cause a tremor and spasms. These effects can be weakened or eliminated with the cholinolytic substances possessing central N - cholinolytic activity (naira., arpenal, Tropacinum, etc.).
m-H olino mimetik are used by hl. obr. in ophthalmology as miotocs (see) for the purpose of decrease in intraocular pressure. At the same time the basic nitriles which are well getting through a conjunctiva, napr, Pilocarpinum and aceclidine have advantage. Resorptive effect of aceclidine is used at an atony of a bladder and intestines. Besides, m cholinomimetics can be applied in quality fiziol. antagonists at poisonings with cholinolytic substances. However at the same time they act more weakly and less for a long time in comparison with anti-cholinesterases-nymi substances. m-Holinomimeti-ki are contraindicated at bronchial asthma, stenocardia, atherosclerosis, went. - kish. bleedings, hyperkinesias, epilepsy and at pregnancy.
At overdose of m-holinomime-tics sharp falling of the ABP, bradycardia, disturbances of a cordial rhythm, profuse sweat, strengthening of a vermicular movement of intestines, a plentiful sialosis and other mu-skarinopodobny symptoms is observed. In quality fiziol. antagonists at poisonings of m cholinomimetics appoint atropine or m-care-nolitiki for others.
From N cholinomimetics in medical practice as reflex stimulators of breath apply lobeline and Cytitonum (see), to-rye cause short-term reflex strengthening of breath due to excitement of chemoceptors of a sinocarotid zone. Sometimes lobeline and Cytitonum use also for determination of speed of a blood-groove (on time which passed from the moment of administration of drug before emergence of the first deep breath). Besides, the drugs containing lobeline and cytisine apply for the purpose of simplification of disaccustoming from smoking (see Tobacco).
n-Holinomimetiki are contraindicated at the expressed organic changes of cardiovascular system and stable arterial hypertension.
At poisonings with nicotine and other N cholinomimetics excitement of c is observed. N of page (in the first phase) with the subsequent paralysis. In case of poisoning with lobeline and Cytitonum vomiting, respiratory depression (after kratkovrekhmenny excitement), toniko-clonic spasms is possible. Physiological antagonists of N cholinomimetics are N cholinolytics and sympatholytics. However they are effective only in a phase of excitement. In a paralytic phase of their action apply means of pathogenetic and symptomatic therapy to treatment of poisonings of N cholinomimetics. Bibliography: And N and h to about in S. V. Selective effect of mediator means, L., 1974; The Goal and S. N. k, the Smith about in
S. G. and 3 and c e p and E. P. Stereospetsifichnost's N of effect of medicinal substances, L., 1973; M and sh to about in with to and y M. D. Le
karstvenny means, p.1, page 215, M., 1984; M and x e l with about ii M. I. and 3 e y m and l E. V. Atsetilkholin, L., 1970; G i e r e n A. a.KokkinidisM. „Activity triangles41 iri crystal structures of cholinergic agonists, Naturwissenschafteri, v. 68, p. 482, 1981;
The pharmacological basis of therapeutics, ed. by A. G. Gilman a. o., N. Y., 1980.