Toxicants of anticholinesterase action: mechanism of action, clinical signs and existing questions of supply by antidotal therapy

  • Authors: L.A. Ustinova, N.N. Seredynska, N.V. Kurdil, V.I. Saglo, M.I. Barasy, O.A. Yevtodiev
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L. Ustinova, N. Seredynskaya, N. Kurdyl, V. Saglo, М. Barasy, O. Yevtodyev

Abstract. The article is devoted to the current problem — the deterioration of the current state of chemical safety in Ukraine, the spread of the use of organophosphorus compounds in agriculture, life, pharmaceutical and chemical industry, its negative impact on human health.
The present state of chemical safety in Ukraine is analyzed. The main threats of poisoning with anticholinesterase-type agents are determined, characteristics of the mechanism of action, clinical signs and means for the treatment of poisoning with anticholinesterases are given. The authors, on the basis of studying the mechanisms of toxic action, provide suggestions on improving the ways of pharmacological correction, raising the issues of development of drugs and the creation of treatment regimens of intoxication of organophosphorus compounds.
Key words: toxicology, chemical safety, organophosphorus compounds, antidotes.

Introduction. The current toxicological situation in Ukraine is characterized by a sharp deterioration of the state of chemical safety. According to the State Emergency Service of Ukraine data, given in the National report on the state of technogenic and natural safety in Ukraine over the past 10 years, thousands of facilities and a significant territory of Ukraine are exposed to dangerous factors of natural and man-made origin, which constantly threaten with emergencies and dangerous events, deaths of people at work and in the everyday life, worsen living conditions of the population, pollute the environment and lead to economic losses.

According to the National Report on the State of Man-made and Natural Safety in Ukraine in recent years, the examples of large-scale emergencies related to the effects of chemicals are as follows:

-    damage caused by the leakage of 15 tanks with yellow phosphorus in Lviv region in July 2007, 160 people were affected in the pollution zone of many kilometres;
-    a fire at the pesticide storage station in Dzhankoy (Crimea) in October 2009, the fire resulted in burning of 160 tons of pesticides (manganese-containing pesticides) that were stored since 1960–1970; the fire area was 600 m2;
-    a fire at the paint and varnish plant in Makiyivka (Donetsk region) in 2012, due to the flash of 14 tankers with solvents, about 40 people were injured;
-    the release of ammonia at the Stirol concern in Horlivka (Donetsk region) in August 2013, there were 6 deaths and dozens of people were injured.

Organophosphorus compounds (OPs), substances of anticholinesterase type of action, are among rather common in the world substances that can be used not only as weapons but also in agriculture, chemical and pharmaceutical industries, everyday life. They may negatively affect the health of people and animals, the environment, getting into the air, water, soil, food. The following fact deserves particular attention: Despite the international agreements on the prohibition of the use of nuclear and chemical weapons, the destruction and non-proliferation of chemical warfare agents (CWA), OPs remain in service in many armies of the world [1-4].

The threat of poisoning with anticholinesterase-type substances is due to many factors, among which: their presence in service in many countries, the spread of terrorism and suicide-related acts with the use of OPs, use in agriculture [5-8], provided that agriculture uses both existing pesticides, and creates new selective ones: highly toxic to pests. These agents have a weak ACE inhibitory activity for the vertebrates and humans, which aggravates the timely diagnosis of poisoning and complicates treatment [9-11].

OPs were used several times during the last decade of the last century in Japan in terrorist acts [4]. The military personnel in the Persian Gulf were exposed to the toxicants among which there were also OPs, as evidenced not only by the results of the identification of these compounds in the zones of chemical pollution, but also the clinical signs of intoxication, identified with the manifestations of remote and chronic effects of intoxication with low doses of these compounds, including warfare [4, 6].

The peculiarities of OPs effect caused by high toxicity, polyapplication and rate of action, as well as the current state of not perfect means of delivering poisons to a bioobject (both to a group of people and to an individual) may lead to unpredictability of the action of toxicants. If various doses of poisons entered the body. The diagnosis and treatment of victims who have suffered intoxication with anticholinesterases are complicated.

The aforementioned became the basis for the generalization of modern features of the mechanism of action, clinical signs and provision of antidotes in case of intoxication with toxicants of anticholinesterase action on a national basis.

Purpose of the study: a generalization of modern features of the mechanism of action, clinical signs and provision of antidotes in case of intoxication with toxicants of anticholinesterase action.

Object and methods of study. The analysis of publications on the peculiarities of the mechanism of action, clinical signs and problems of the provision of antidotes in Ukraine over the past 20 years has been carried out. The recommendations of the International Program on Chemical Safety of the World Health Organization on the development of the national list of antidotes used in the treatment of acute poisoning have been worked out. The latest resolutions of the Cabinet of Ministers of Ukraine and the orders of the Ministry of Health of Ukraine regulating the National List of Essential Medicines, in particular, section 4 (Antidotes and other substances used in poisoning with anticholinesterase toxicants) have been reviewed.

Study results. A special group of substances, most of which are toxic to humans, are pesticides that are intended to control pests in agriculture and weeds. Among them, organophosphorus compounds occupy the leading position. Dangerous chemicals are stored throughout Ukraine (in Lviv, Ivano-Frankivsk, Vinnytsia, Rivne, Kyiv, Cherkasy, Sumy, Dnipro, Zaporizhzhia, and Kharkiv).

The ongoing hostilities in the East of Ukraine have a negative impact not only on the industrial production in these areas, they are a major factor in increasing the level of chemical danger in the region. Upon the active development of the military situation in Donbass, the problem of large-scale destruction of potentially dangerous objects and objects of critical infrastructure, in particular warehouses, storage facilities and storage sites of pesticides containing anticholinesterase-type substances, is pressing. The probable consequences of such a situation include pollution of the environment, poisoning of military and civilians.

OPs toxicity leads to severe, often irreversible changes in the functioning of vital organs and systems, and when using warfare OPs, these changes are generally incompatible with life [7, 4, 42]. Dysfunction of vital organs and systems arise both through the physical and chemical properties of OPs, and mechanisms of their action. The main mechanism of action of OPs is the inhibition of the activity of the enzyme cholinesterase [11-13], which caused not only the name — anticholinesterases but also the direction of research on the development of therapies to overcome lesions. The anticholinesterase cholinomimetic effect of OPs leads to toxic excitation of cholinoreactive systems by accumulation in the synapse of the main neurotransmitter of the peripheral and central cholinergic AC transmission, that is, OPs poisoning of is poisoning with one’s own AC [13, 14, 15]. The transport of OPs molecules through the membrane of the histo-hemic barrier also occurs through diffusion, and the speed and direction of diffusion depend on the magnitude of complementarity of the ligands to the sites of their specific binding [16].

AC excitation of M-cholinoreceptors results in miosis, intraocular pressure decrease, accommodation spasm, activation of peristalsis of the stomach and intestine, stimulated secretion of the tear, salivary, gastric and pancreas, reduction of the smooth muscle of bronchioles, bladder, bradycardia, decreased cardiac output, hypotension, desynchronization of the electroencephalogram. Excitation of H-cholinoreceptors leads to the action potential in the end plate and in the ganglia, stimulation of the respiratory and vascular centres, the release of catecholamines [17]. Induction of the nicotinic receptors of the extrapyramidal cholinoceptive system causes tremor, ataxia, rigidity of muscles, convulsions, and the excitation of the H-cholinoceptive structures of the peripheral nervous system leads to hyperthermia, tachycardia, hypertension. Thus, the main mechanism of action of OPs to a large extent leads to the development of clinical and biochemical signs of intoxication.

Anticholinesterase substances cause miosis, salivation, muscle fasciculations, seizures, bronchorrhea, impaired neuromuscular transmission [18], which, of course, is related to the cholinoceptivity of these compounds [19]. Farmworkers in many countries of the world [20] demonstrated skin irritation of the extremities, conjunctiva, headache, twitching of the neck muscles, lacrimation, difficulty breathing, hypersalivation, diarrhoea, excitability, sleep disturbance, where the manifestation and intensity of clinical signs of intoxication does not always correlate with ACE activity [21].

Symptoms of intoxication of tragedies in Japan [4] following the use of sarin of the Aum Shinrikyo sect (1994) and the use of this poison in the Tokyo Metro (1995) were accompanied with severe myosis, decreased visual acuity, conjunctival hyperemia, ophthalmalgia and pain around the eye socket, accommodation spasms, reduced intraocular pressure, non-rhythmic superficial breathing, nausea, vomiting, salivation, tearing, numbness of fingers, bronchorrhea, muscle weakness, and in some cases, fasciculations, bronchospasm, neuromuscular transmission disorder , seizures, acute respiratory failure and coma. The literature presents also symptoms of OPs poisoning in suicide acts that are identical to the above-mentioned. The most significant complications of such poisonings were pneumonia, acute renal failure and heart failure [22].

Considering the main mechanism of OPs action and clinical signs of intoxication, agents normalizing the functioning of the cholinergic mediator system, in particular, M-choline blockers and acetylcholinesterase reactivators, as well as anticonvulsants [23-24] are used for the treatment of poisoning with anticonvulsant agents. This applies to both organophosphorus pesticide poisoning and possible poisoning with the use or destruction of NBC weapons, including OPs that can be used in terrorist activities.

The widely known anticholinergic agent is atropine, which is included in the 19th List of Essential Medicines (Section 4. Antidotes and other substances used in poisoning, subsection 4.2. Specific antidotes) approved by the Cabinet of Ministers of March 16, 2017, No. 180.

Table 1

Antidotes and other substances used in poisoning, included in the 19th List of Essential Medicines (Section IV)

It should be noted that although in the 19th National List of Essential Medicines, in comparison with the 18th List, 6 additional names were added to the section of antidotes (12 names in total) with anticholinergic atropine included, but it does not fully prevent the mortality of all victims, does not contribute to the normalization of vital organs and systems, and, conversely, may lead to deterioration of the cardiovascular system functioning, in particular.

In the West, in the 80’s of the last century, an acetylcholinesterase reactivator (the so-called HI-6) was synthesized, which showed not only a preventive but also a therapeutic effect, was introduced into the manufacturing industry and provision of armies. Acetylcholinesterase reactivators, mainly oximes (pralidoxime, obidoxime) are foreign medicinal products which are not produced in the territory of our country. Developments (scientific) of new acetylcholinesterase reactivators were carried out in Ukraine at some research institutes in the time of the Soviet Union; they were close to real completion because the results of scientific studies proved the high efficacy of new compounds and the possibility of clinical application [25]. 

Researchers from all over the world up until now are searching for ways of pharmacological correction and development of medicinal products, the creation of treatment schemes for intoxications.
The issue of the development and production of acetylcholinesterase reactivators in independent Ukraine is constantly the main focus for a long time. There are many works devoted to a variety of medicinal products that can be used as antidote therapy [26-29].

Some of the similar achievements were investigated in Ukraine at some point. It has been shown that to normalize cerebral blood flow and cardiovascular activity, it is advisable to use modulators of the histaminergic system. GABA-ergic transmission is greatly facilitated by pyridostigmine; the effect of Zoman on GABA-ergic processes is blocked in the presence of selective M2- and M3-cholinoreceptor antagonists and a non-specific atropin antagonist [30], which confirms the interaction of cholinergic and GABA-ergic mediator systems and justifies the need for a study of this direction of pharmacological correction for intoxication with OPs. To eliminate convulsive syndrome, it may be effective to use GABA-ergic antagonists. Antiserotonin agents (ketanserin) exert a preventive effect in acute poisoning, which is accompanied by pulmonary respiration dysfunction, pulmonary oedema, but the use of α- and β-blockers affects negatively. It is believed [311] that the regulation of AC release in case of intoxication with soman by adenosine A1 receptor agonists is an effective approach to pharmacological therapy of OPs. Adenosine receptor agonists may be effective during the manifestation of convulsions [32], their administration is promising for the normalization of ACE activity as well [33]; they prevent the death of animals and correct the activity of the cardiovascular system in case of poisoning with sarin [34].

Piracetam and diazepam significantly improve memory, physical endurance, higher nervous activity, with diazepam showing some efficacy in preventing the death of animals [35]. The agents that increase RNA synthesis, affect protein metabolism may be used by pharmacological correction of the protein synthesis function [36]. In addition, these agents, as well as A1-adenosine receptor agonists, may reduce the strength and duration of convulsions associated with OPs poisoning. The study of the efficacy of enzymes, in particular, paraoxonergidrolase, which reduces the effect ACE reinhibition under the action of VX, soman, and sarin [37] indicates the need for correction of OPs toxic effects. In particular poisoning with paraoxon results in parotitis, when there is hyperamylasemia, so the correction of this enzyme chain can also be effective in OPs intoxication. It is recommended to start treatment of pancreatitis as soon as possible in case of intoxication [38].

Normalization of protein synthesis and detoxification functions of the liver is associated with the need for the normalization (activation) of NO synthesis. The main role in dearylation and desulphuration of OPs (chlorpyrophos, in particular) belong to isoforms P450 [39].

Membrane-active antioxidants are believed to be promising agents, as they may directly affect the physicochemical properties and functional activity of biological membranes by modulating the receptor function and activity of membrane-bound enzymes [89, 90]. Infusion preparations based on perfluorocarbon compounds can be used via pharmacological correction of rheological characteristics of membranes of erythrocytes and cytochemical features of neutrophil granulocytes [40]. The normalization of the blood gas transport function with the help of perfluorane may significantly improve the condition of animals in case of OPs intoxication, reduce mortality and increase the efficacy of traditional antidotes [41]. Data on the need for correction of the blood gas transport function, gas exchange in the lungs, and consumption of oxygen by the myocardium indicate the normalization of cardiohaemodynamics against hypoxia developing with malathion poisoning, which by the way, like other OPs, is attributed to cardiotoxic poisons. Elimination of hypoxic syndrome can normalize the content of HA, cAMP in the rat brain, in particular [42]. β-adrenoceptor agonist alupent can normalize pulmonary blood flow to a certain extent, which is used in conjunction with budaxime, self- and buddy aid antidote. The need for pharmacological correction of energy metabolism, stabilization of levels and activity of ATPases with CWA injuries is due to data on the wave-like toxicity of a change in Na+, K+ -ATPase levels over time. The therapeutic effect of anti-shock agents (thomersol) is observed with carbofosis poisoning [43].

The formation of immune complexes and their elimination by phagocytosis can apparently be the direction of pharmacological correction, aimed at normalization of immune processes [44]. In addition, taking into account the information on the cholinergic component of OPs mechanism of action and analysing the data presented, it is appropriate to emphasize that the secondary intermediaries of the biochemical response of the cell during stimulation of the cholinoreceptors are Ca2+, K+, Na+, products of metabolism of phosphatidylcholine, cGMP; that there are a number of agents that inhibit the release of catecholamines, among which are α-adrenergic agonists and M-cholinoreceptors, prostaglandins, local anaesthetic agents, adrenergic neuron blockers. The indicated agents act on Ca2+, which initiates secretion [45, 46].

Therefore, it is important to study not only the interaction of products with one (specific) type of a receptor, but also direct the research to study the various stages of transformation of the molecular signal into the biochemical and physiological cell response, because each of these stages can be a target not only for the action of agents but also for the action of toxicants.

A new class of agents is expected to appear that can act on the inter-receptor level and moreover, calcium current antagonists may be used for this purpose, which exercises their influence by interacting with numerous types of receptors [17]. In our opinion, such an attitude should be taken into account when assessing, in fact, the actions of OPs on the functioning of various bodies and systems. These compounds, as mentioned above, are characterized by polytropic (multisystemic) action; it is anticholinesterases that mediate their effects through numerous receptor formations; an intermediary of the biochemical response of cells, which eventually forms a function, is, unquestionably, Ca2+.

The given literary data indicate the lack of knowledge of the mechanism of toxic effects of OPs, which results in the lack of effective means of treatment of intoxication.


Thus, there is an important problem of modern toxicology. It is caused by complicated processes, in particular, the rapid arming of the world armies, the spread of anticholinergic toxicants in agriculture, the pharmaceutical and military industries, the possibility of use in terrorist and suicidal purposes, as well as high toxicity, rate and polytopy of numerous chemical agents. Insufficient knowledge of mechanisms for exerting their toxic effects on various organs and systems prompts active research of these mechanisms in order to develop new, more effective means, capable of influencing various parts of pathogenesis of poisoning, pharmacological correction and prevention of acute and late manifestations of intoxication for the purpose of protection and preservation not only the military (personnel) health, but also the civilian population of different age groups, occupations, etc. It is necessary to provide appropriate services of the country with an adequate quantity of qualitative antidotes.

The above information, in our opinion, should become a compelling motivation for solving urgent scientific and practical problems in the field of toxicology, medical protection of the army and civilian population, in particular the issue of training scientific personnel for conducting such researches, as well as medical workers to ensure the proper level of phased medical assistance to different categories of the population of the country.



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