ANTIKHOLINESTERAZNY MEANS — the connections braking activity of cholinesterases. In tissues of animals and the person there are several cholinesterases (see). The major physiological importance has oppression of true cholinesterase — the acetylcholinesterase (AHE) which is contained in nervous cells, erythrocytes and in many fabrics. False cholinesterase — butyrylcholinesterase (BuHE) of a blood plasma and fabrics — can be slowed down almost completely without serious violation of physiological functions of an organism.
Ampere-second. distinguish on selectivity of their action. Some A.c. — physostigmine (see), prozerin (see) — AHE and BuHE approximately equally oppress. Others selectively oppress AHE, napr, bromide of a N-p-chlorophenyl-methyl-carbamic ester of m - oxyphenyl - three - methylammonium (No. 1250), dimethoiodide encore - (piperidinometilkumarinil-5) - ketone (3318 CT), methylsulfomethylate О-этил-S-β-этилмеркаптоэтилозого of an ester methane-phosphonic to - you are (State Duma-42), etc. Bromide of a dimethylcarbamic ester 2-oxy-5-phenyl-Benzylium-trimetilammoniya (No. 683), diizopropilftorfosfat (DFF), a 0,0-diethyl-S [β-(tsiklogeksilmetilamino) - ethyl] - thiophosphate (GT-106), etc. BuHE oppress stronger.
On reversibility of the oppressing action on cholinesterases distinguish Ampere-second. reversible action — carbamates (physostigmine, prozerin, sevin, etc.), Galantaminum (see) and some quaternary ammonium compounds (edrofoniya, benzokhinoniya, 3318 CT, etc.) and irreversible action — some derivatives phosphoric and phosphonic acids (organophosphorous connections — FOS): Arminum (see), Nibuphinum (see), pirofos (see), Phosphacolum (see), hlorofos, octamethyl, State Duma-42, GT-106, sarin, GD, DFF, etc.
Ampere-second. cause narrowing of a pupil, decrease in intraocular pressure and a spasm of accommodation. At action on went. - kish. a path stimulate motility and partly secretion of glands. Ampere-second. strengthen reductions of a uterus and a bladder, raise a tone of muscles of bronchial tubes, strengthen secretion of glands with a cholinergic innervation: salivary, lacrimal, sweat, mucous glands of respiratory tracts. Action of Ampere-second. on cardiovascular system less definitely. On the one hand, Ampere-second. can reduce arterial pressure, increasing a tone of parasympathetic nerves, and also reducing a tone of sympathetic vasoconstrictors (thanks to direct action by vasomotor centers), with another — can cause pressor effect, facilitating cholinergic transfer of excitement in sympathetic gangliya, and also increasing release of adrenaline marrow of adrenal glands. On the central nervous system of Ampere-second. have usually stimulating, exciting effect, a cut it is connected with stabilization of acetylcholine in cholinergic synapses of bark and other departments of a brain. The central action is especially strongly expressed at Ampere-second., well soluble in lipoida (physostigmine, DFF, etc.) Ampere-second., having constant positive charge in a molecule (prozerin, the State Duma-42, octamethyl), badly get through a blood-brain barrier; in usual doses they do not brake cholinesterase of a brain and have no central effect. Braking of activity of cholinesterases leads to accumulation of acetylcholine in those synapses where it is a mediator of nervous excitement. At the same time there is an excitement of all cholinergic systems. At introduction of toxic doses of Ampere-second. after excitement there can come disturbance of carrying out in cholinergic synapses.
Interaction of inhibitors with cholinesterases happens as interaction of substrate (acetylcholine) to cholinesterases. The first phase — formation of a reversible complex enzyme — substrate (Mikhaelns's complex); the second phase — acylation of enzyme, i.e. formation of a covalent bond between acyl (acetyl) group of acetylcholine and a hydroxyl of serine in the esteratichesky center of cholinesterase; the third phase — deacylation with recovery of reactivity of enzyme. In case of interaction of acetylcholine with cholinesterase all three phases proceed very quickly. Quaternary ammonium compounds are truly reversible inhibitors: their action is limited only to the first phase — formation of a reversible complex; acylation of enzyme does not happen. At action of carbamates all three phases take place: after formation of a complex there is an acylation (karbamilirovaniye) of enzyme, and then a dekarbamilirovaniye. Thus, braking is almost reversible. However the dekarbamilirovaniye occurs incomparably more slowly, than deacetylation, and it slows down reaction of cholinesterase with acetylcholine. At action of FOS after formation of a complex there is an acylation (phosphorylation) of enzyme too, however the third phase (dephosphorylation) in usual conditions proceeds so slowly that braking is almost irreversible. Durability of connection depends on chemical constitution of the phosphorylating group (e.g., DFF containing 0,0-diisopropyl-fosforilnuyu group forms much stronger communication with enzyme, than its analog containing 0,0-dimethyl-fosforilnuyu group).
Recovery of activity of fosforilirovanny cholinesterases can be reached use of reaktivator. At action of many FOS activity of cholinesterase is recovered (without use of reaktivator) practically only by synthesis of new enzyme. Duration of effect of these substances and their cumulative action is connected with it. BuHE of serum is synthesized in a liver. Its activity reduced by organophosphorous Ampere-second., it is recovered within several weeks, but at diseases of a liver recovery can strongly be slowed down. The recovery rate of activity of AHE of erythrocytes matches the speed of their regeneration. Recovery of activity of AHE of muscles and a brain happens within several months.
Action of Ampere-second. is defined on various bodies and systems generally by their property to protect acetylcholine from destruction. Therefore it usually matches effects of excitement of cholinergic nerves and substantially depends on their tone. E.g., narrowing of a pupil under the influence of physostigmine is possible only on condition of excitement of a third cranial nerve. Action of Ampere-second. on bodies with a cholinergic innervation after their denervation does not develop. Some Ampere-second. in high toxic doses can have also direct cholinomimetic effect.
Ampere-second. widely use in medicine at treatment of glaucoma, for the prevention and treatment of a postoperative atony of intestines, a bladder (prozerin, physostigmine), for acceleration of childbirth at weakness or total absence of patrimonial activity (postmature pregnancy), for treatment of myasthenia gravis. Ampere-second. (physostigmine, Galantaminum) are valuable cure of recovery therapy for diseases of c. N of page (the residual phenomena after disturbance of cerebral circulation, etc.). Physostigmine and prozerin is used also as the main antidotes at poisoning with cholinolytic substances — atropine, a curare, etc. Organophosphorous Ampere-second. (pirofos, oktametiltetramidopirofosfat, hlorofos, etc.) widely apply as insecticides to pest control of agriculture, and also with household insects. Organophosphorous Ampere-second. work it is long and for a long time increase sensitivity to a prozerin, however quite often have side effect: make sick, vomiting, pains in an anticardium.
Overdose of Ampere-second. can cause poisonings. The main symptoms of poisoning — narrowing of a pupil (especially at effect of vapors of flying Ampere-second. on an unprotected eye), a severe headache, the complicated breath owing to a bronchospasm, abdominal pains, a diarrhea, hypersalivation, fascicular twitching of any muscles, difficulty of the speech, excitement, sensation of fear. At a serious poisoning — severe suffocation, spasms, a loss of consciousness, an involuntary urination and defecation. Death comes from an apnoea, edges can be connected with paralysis of a respiratory center, a strong spasm of bronchial tubes, and also with disturbance of carrying out nervous impulses on respiratory muscles. At hron, poisonings of Ampere-second. narrowing of a pupil, headaches, periodically arising difficulty of breath, the general weakness, irritability are noted. Objective criterion of weight of poisoning is decrease of the activity of cholinesterase (especially AHE) blood: at hron, poisonings — for 25 — 50%, at acute — for 90%.
For treatment of acute poisoning of Ampere-second. apply reaktivator of cholinesterase in a combination with cholinolytics: 15% solution of a dipiroksim of 1 — 2 ml subcutaneously or intramusculary, 0,1% solution of atropine of 2 — 3 ml subcutaneously. It is possible to use also Tropacinum, amizyl and other cholinolytics. At a serious poisoning — an artificial respiration and repeated introduction of reaktivator of cholinesterase and atropine (3 ml) intravenously before emergence of symptoms of reatropinization.
Ampere-second. are contraindicated at epilepsy, hyperkinesias, bronchial asthma, stenocardia, the expressed arteriosclerosis.
Antikholinesterazny means in the medicolegal relation
Diagnosis of poisonings of Ampere-second. it is based on clinical symptoms, and also on definition of activity of cholinesterase of blood. In case of death at poisoning of Ampere-second. at external examination of a corpse quickly coming, strongly expressed cadaveric spasm and a miosis is noted. During the opening find symptoms of asphyxia: blood liquid, dark red; under serous covers (an epicardium, a pleura) — punctulate hemorrhages; in a gleam of respiratory tracts — the made foam slime that testifies to hypersecretion of their glands, also signs «отшнуровывающейся» a vermicular movement of intestines are noted. In case of the severe spasms preceding death the partial or full separation of separate muscles is possible (rather seldom).
At a histologic research of internals, except symptoms of asphyxia, find a spasm of unstriated muscles of intestines and bronchial tubes. At a research of bodies and fabrics of a corpse on holinesterazny activity note its decrease.
See also Poisonings (in the medicolegal relation).
Bibliography: S. N's brooms, and P about z e V. I N metal. Cholinesterases and anti-sincaline-esteraznye of substance, L., 1964, bibliogr.; Michelson M. Ja., etc. Antikholinesterazny substances, the Management on pharmakol., under the editorship of N. V. Lazarev, t. 1, page 205, L., 1961, bibliogr.; O'B r and y N of River. Toxic ethers of acids of phosphorus, the lane with English, M., 1964, bibliogr.; Saunders B. Chemistry and toxicology of organic compounds of phosphorus and fluorine, the lane with English, M., 1961, bibliogr.; Chemistry and use of organophosphorous connections, under the editorship of M. I. Kabachnik, M., 1972, bibliogr.; Anticholinesterase agents, ed. by A. G. Karczmar, Int. Encyclopedia Pharmacol., sect. 13, v. 1, Oxford, 1970; Cholin-esterases and anticholinesterase agents, Handb. exp. Pharmakol., begr. A. Heffter, Bd 15, B. u. a., 1963, Bibliogr.
Ampere-second. in the medicolegal relation — Smusin Ya. S. Forensic medical examination of poisonings of anti-cholinesterases-nymi with substances, M., 1968, bibliogr.; Tumanov A. K. and Tomilinv. B. Hereditary polymorphism of isoantigens and enzymes of blood is normal also of pathology of the person, M., 1969, bibliogr.
E. V. Zeymal, M. Ja. Michelson; A. K. Tumanov (court.).