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Review Article Anatomy Physiol Biochem Int J Volume 1 Issue 2 - October 2016 Copyright © All rights are reserved by Vivek Kumar Gupta

Alleviation of Acute Poisoning of in Humans

Vivek Kumar Gupta1 and Bechan Sharma2* 1Department of Biochemistry, University of Allahabad, India 2Department of Biochemistry, University of Allahabad, India Submission: September 25, 2016; Published: October 12, 2016 *Corresponding author: Bechan Sharma, Department of Biochemistry, University of Allahabad, Allahabad-211002, India, Tel: ; E-mail:

Abstract Organophosphates (OPs) are used as and developed as warfare nerve agents. Exposure to an could be lethal resulting in death due to respiratory failure. The mechanism of organophosphate poisoning includes inhibition of the acetyl (AChE) via phosphorylation of the hydroxyl group of present at the active site of the . The inhibition of acetyl cholinesterase (AChE) results in the accumulation of (ACh) at receptor sites, producing continuous stimulation throughout the nervous systems. Several therapeutic agents have been developed and used in the treatment of poisoning with OPs. For example, pyridiniumoximes have been developed as therapeutic agents for the treatment of poisoning by OPs. The mode of action of pyridiniumoximes is by the reactivation of inhibited acetyl cholinesterase. However, the universal broad spectrum capable of protecting against all known OPs, is still have to be investigated. Presently, a combination of an antimuscarinic agent, e.g. , an AChE reactivators i.e. oximes and are used for the treatment of organophosphate poisoning in humans. In spite of enormous efforts devoted to the development of new AChEreactivators as against poisoning with organophosphates, only four compounds so far have been found their applications in human medicine. This article presents an updated account of the available reports concerning the treatment of OP poisoning and its alleviation.

Keywords: Pesticides; Organophosphate poisoning; ; Acetyl cholinesterase; Cholinergic; Alleviation

Abbreviations: OP: Organophosphate; AChE: ; ChE: ; Ach: acetylcholin

Introduction The esteraticsubsite contains the catalytic triad of three Acetylcholinesterase (AChE) (EC 3.1.1.7) is the primary amino acids: serine 200, 440 and glutamate 327 similar cholinesterase belongs to carboxylesterase family . It is an to the triad in other serine proteases except that the glutamate acetylhydrolase, found in many types of conducting tissues. AChE is the third member rather than aspartate, where acetylcholine is also found on the red blood cell membranes and blood plasma is hydrolyzed to acetate and [8]. The hydrolysis reaction (EC 3.1.1.8, ChE) [1]. The function of AChE is the termination of of the carboxyl ester forms an acyl-enzyme and free choline. ACh at the junctions of the various cholinergic nerve endings Then, the acyl-enzyme undergoes nucleophilic attack by a water with their post-synaptic sites which catalyzes the breakdown molecule, assisted by the histidine 440 group, liberating acetic of acetylcholine that function as neurotransmitters with very acid and regenerating the free enzyme [9,10]. The mechanism high catalytic activity. The turn over number for AChE has been of action of AChE has been elucidated in (Figure 1). The anionic found to be about 25000 molecules of acetylcholine (ACh) sub site accommodates the positive quaternary amine of hydrolysed per second [2]. The AChE activity is higher in motor acetylcholine and other cationic substrates and inhibitors. The neurons than in sensory neurons [3,4]. AChE exists in multiple cationic substrates are not bound by interaction of 14 aromatic molecular forms with different oligomeric assembly but having amino residues [11], which are highly conserved across different the same catalytic activities. The enzyme has been reported to species [12]. Among these aromatic amino acids the substitution be membrane bound [5-7]. The active site of AChE has two sub of tryptophan 84 with alanineresults in a 3000-fold decreased sites - anionic site and esteraticsubsite. reactivity [13]. During neurotransmission, ACh is released

Anatomy Physiol Biochem Int J 1(2) : APBIJ.MS.ID.555558 (2016) 040 Anatomy Physiology & Biochemistry International Journal from presynaptic neuron into synaptic cleft and binds to ACh The physiological role of AChE in blood is not understood, but receptors on the post-synaptic membrane, relaying the signal. it was proposed that ChE may have roles in neurotransmission AChE, also located on the post-synaptic membrane, terminates and involved in other nervous system functions and in the signal transmission by hydrolyzingACh. The liberated neurodegenerative disorders [17]. In the presence of OPs, AChE choline is taken up again by the pre-synaptic neuron and ACh is becomes progressively inhibited and is not further capable synthesized by combining with acetyl-CoA through the action of of hydrolyzing ACh [18]. Consequently, ACh accumulates at choline acetyltransferase [14] (Figure 2). cholinergic receptor sites and produces excessive stimulation of cholinergic receptors throughout the nervous systems. Both substrate and inhibitors react covalently with the esterase in essentially the same manner, because acetylation of the serine residue at AChE catalytic site is analogous to phosphorylation. Inhibited enzyme can be spontaneously reactivated at different rates depending on the inhibitor. The variations in the acute toxicity of OP are the result of their different chemical structures and rates of spontaneous reactivation and aging. The aging has the major clinical importance and an imperative problem Abbreviations: CoA: Coenzzye A; Ach: Acetylcholine; ChAT: Cholineacetyl transferrase; Ch in the treatment of poisoning because aged form of : Choline; Ach: Acetylcholine; AChE: Acetylcholinesterase; R: phosphorylated AChE is resistant to both spontaneous and Receptor; PSM: Post synaptic membrane. -induced reactivation. Hence, recovery of inactivated AChE Figure 1: Mechanism of nerve conduction in synaptic cleft. function depends on relatively slow resynthesis of AChE during aging thereby exerting higher level of toxicity as compared to those at younger age. Clinical presentation of OP poisoning Figure 2: Catalysis of acetylcholine hydrolysis by AChE. According to World Health Organization (WHO), in cases of intoxication the signs and symptoms of acute poisoning with OPs are predictable from their levels of AChE activity [19]. These clinical features include sweating, lacrimation, rhinorrhea,

dyspnea, cough, wheezing, fasciculations, bradycardia, and abdominal cramps, salivation, respiratory difficulties, change in ECG, cyanosis, anorexia, nausea, , diarrhea, involuntary urination and defecation, accompanied by dizziness, tremulousness, confusion, ataxia, headache, tremors, Abbreviations: AS: Anionic subsite; ES: Esteraticsubsite. constriction sensation in the chest, twitching of facial muscles Figure 3: Mechanism of inhibition of AChE by inhibitors and reactivation of AChE by oximes. that even after survival of the patient with OP poisoning, there and tongue, and fatigability finally into death. It has been reported Organophosphates (OPs), the esters of phosphoric acid, are a would be mood swings, personality changes, aggressive events class of irreversible AChE inhibitors. The cleavage of OP by AChE and psychotic episodes [20,21]. Diagnosis is relatively based on leaves a phosphoryl group in the esteratic site, which is slow medical history, exposure circumstances, clinical presentation, to be hydrolyzed and can bound covalently. , esters and laboratory tests. Erythrocyte AChE is identical to the enzyme of N-methyl carbamic acid, are reversible inhibitors of AChE present in the target synapses and its levels are assumed to that hydrolyze in hours and occupy the esteratic site for short periods of time (Figure 3). Presently, a combination of AChE AChE may be considered as a biomarker of neurotoxicity. Due reactivators such as atropine and diazepam are used for the reflect the effects of OPs in target organs. Thus, erythrocyte treatment of OP poisoning. The drugs , , to pharmacokinetic reasons, it is difficult to know exactly, how and used in alzheimer disease are inhibitors of the nervous system since access to blood is always easier than AChE [9,15]. It has also been reported that some phytochemicals closely the AChE inhibition in erythrocytes reflects to that in such as , the active ingredient of , a different message from that in brain [18]. is a competitive inhibitor of AChE [16]. This article presents brain. Thus, erythrocytes AChE inhibition may reflect altogether an updated account of the reports available concerning the Treatment of acute poisoning with Organophosphorus alleviation of OP poisoning by some antidotes including atropine pesticides and oximes. Treatment of OP should begin with decontamination and care must be taken not to contaminate Interaction of cholinesterases with organophosphates others.

How to cite this article: Vivek Kumar G, Bechan S. Alleviation of Acute Poisoning of Organophosphates in Humans. Anatomy Physiol Biochem Int J. 0041 2016; 1(2) : 555558. DOI: 10.19080/APBIJ.2016.01.555558. Anatomy Physiology & Biochemistry International Journal

Atropine attack victims in 1995 [30]. However, PAM-2 should not be recommended against poisoning with warfare nerve agents due Atropine acts through blocking the effects of excess concentrations of acetylcholine at cholinergic synapses following OP inhibition of AChE. It has been reported that atropine may toObidoxime its lack of efficacy [31]. prevent development of convulsions and brain damage induced when administered to humans by intramuscular by certain OP [22]. The trial dose of atropine is 0.05 mg/kg route, it produced a plasma concentration >4 mg/L, from 5 min intravenously, should be given slowly over 3 min, and then after injection to 3 h [32]. Following high doses of obidoxime in repeated every 5–10 min. In symptomatic children, intravenous severely OP poisoned patients; occasional hepatotoxic effects dose of 0.015–0.05 mg/kg atropine should be administered at have been observed including increased serum transaminases interval of every 15 min. Atropine may then be repeated at 15– and jaundice [33]. 30 min intervals until the patient is atropinized (dilated pupils, Asoxime (HI-6) further treatment. Asoxime is considered to be a very promising dry skin, and skin flushing) which should be maintained during Diazepam bispyridiniumoxime in treatment following exposure to most nerve agents. Studies showed that Asoxime dosed by Benzodiazepines are central nervous system (CNS) intramuscular route reached plasma concentrations >4 mg/L depressants, anxiolytics (antipanic or antianxiety agent) in 4–6 min [34]. According to Jovanovi´c et al. [35] asoxime did and muscle relaxants. Marrs [23] in has reported that not show any adverse effect on humans. The only disadvantage benzodiazepines, including diazepam, alter GABA binding in of asoxime compared to other available oximes is its lack of an allosteric fashion. The recommended dose of diazepam in stability in aqueous solutions. Asoxime was considered to be cases of OP poisoning is 5–10mg intravenously in the absence an effective antidote in treatment of patients poisoned with OP of convulsions and 10–20mg intravenously in cases with [34]. convulsions [22]. Conclusion Oximes The management of acute Organophosphate pesticide The antidotal potency of pyridiniumoximes is primarily poisoning in humans includes general (decontamination and attributed to their ability to reactivate phosphorylated cholinesterases. Reactivation proceeds through the formation of oximes (, trimedoxime, obidoxime, and asoxime) intermediate Michaelis-Menten complex leading to the formation supportive measures) and specific treatment with atropine, and diazepam. Since the introduction of the antidotes in treating of stable phosphoryl residue bound to the hydroxyl group of the patients poisoned with OPs, there is still no agreement serine present at active site of AChE. The rate of reactivation on how these substances should be given for the best result depends on structure of phosphoryl moiety bound to the enzyme, following treatment. While the use of atropine and diazepam source of the enzyme, rate of post inhibitory dealkylation and in humans have been widely accepted throughout the world., concentration of oxime [24,25]. Pyridiniumoximes are effective Pyridiniumoximes were successful in the treatment of most in the peripheral nervous system, but also have a penetration cases of OP poisoning, when given with atropine and diazepam. across the blood–brain barrier [26] and therefore enable passage However, some reports indicate that treatment with pralidoxime of higher oxime concentrations into brain [27]. Pralidoxime of oxime treatment may be solved in randomized clinical trial(s) poisoning [28]. The inadequate initial treatment with oximes was not sufficiently beneficial. These problems of effectiveness is not sufficiently effective in the treatment of OP pesticide comparing the WHO-recommended regimen with a placebo to assess the value of pralidoxime, and other oximes (obidoxime, are rapidly cleared from the body. Among the many classes of may not be sufficiently effective in OP poisoning because oximes trimedoxime, and Asoxime) as well, in acute poisoning with OPs. oximes investigated with clinical application can be divided in following groups: monopyridinium (PAM-2, pralidoxime), Acknowledgement bispyridiniumoximes (TMB-4, trimedoxime), obidoxime (LuH-6, Vivek Kumar Gupta is grateful to the University Grant Toxogonin) and asoxime (HI-6).

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How to cite this article: Vivek Kumar G, Bechan S. Alleviation of Acute Poisoning of Organophosphates in Humans. Anatomy Physiol Biochem Int J. 0043 2016; 1(2) : 555558. DOI: 10.19080/APBIJ.2016.01.555558. Anatomy Physiology & Biochemistry International Journal

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How to cite this article: Vivek Kumar G, Bechan S. Alleviation of Acute Poisoning of Organophosphates in Humans. Anatomy Physiol Biochem Int J. 0044 2016; 1(2) : 555558. DOI: 10.19080/APBIJ.2016.01.555558.