Editing Nerve agent (section)

==Biological effects==
Nerve agents attack the [[nervous system]]. All such agents function the same way resulting in [[cholinergic crisis]]: they [[Enzyme inhibitor|inhibit]] the enzyme [[acetylcholinesterase]], which is responsible for the breakdown of [[acetylcholine]] (ACh) in the [[synapse]]s between nerves that control whether muscle tissues  are to relax or contract. If the agent cannot be broken down, muscles are prevented from receiving 'relax' signals and they are effectively paralyzed.{{sfn|Sidell|1997|pp=131–139}} It is the compounding of this paralysis throughout the body that quickly leads to more severe complications, including the heart and the muscles used for breathing. Because of this, the first symptoms usually appear within 30 seconds of exposure and death can occur via [[asphyxia]]tion or [[cardiac arrest]] in a few minutes, depending upon the dose received and the agent used.<ref name="ATSDR" />

Initial symptoms following exposure to nerve agents (like [[Sarin]]) are a runny nose, tightness in the chest, and [[miosis|constriction of the pupils]]. Soon after, the victim will have difficulty breathing and will experience nausea and salivation. As the victim continues to lose control of bodily functions, involuntary [[salivation]], [[tears|lacrimation]], [[urination]], [[defecation]], 
[[gastrointestinal]] pain and [[vomiting]] will be experienced. [[Blister]]s and burning of the eyes and/or lungs may also occur.<ref>{{Cite web | url = http://www.newenv.com/Chemical_and_Biological_Agents.htm | publisher = New Environment Inc. | title = Chemical and Biological Agents | archive-url = https://web.archive.org/web/20170601102557/https://www.newenv.com/resources/chemical_and_biological_agents/ | archive-date = 2017-06-01 | url-status = dead | access-date = 2018-03-08 }}</ref><ref name="ITI">{{cite web | url = http://www.tpub.com/content/advancement/14145/css/14145_203.htm | title = Effects of Blister Agents | work = Integrated Publishing, Inc. | archive-url = https://web.archive.org/web/20170408091413/http://navyadvancement.tpub.com/14145/css/Effects-Of-Blister-Agents-203.htm | archive-date=2017-04-08 | url-status = live | access-date = 2018-03-08 }}</ref> This phase is followed by initially [[myoclonic jerks]] (muscle jerks) followed by [[status epilepticus]]–type epileptic seizure. Death then comes via complete respiratory depression, most likely via the excessive peripheral activity at the [[neuromuscular junction]] of the [[thoracic diaphragm|diaphragm]].{{sfn|Sidell|1997|pp=147–149}}

The effects of nerve agents are long lasting and increase with continued exposure. Survivors of nerve agent poisoning almost invariably develop chronic neurological damage and related [[psychiatric]] effects.<ref name=pmid4838227>{{cite journal | vauthors = Sidell FR | title = Soman and Sarin: clinical manifestations and treatment of accidental poisoning by organophosphates | journal = Clinical Toxicology | volume = 7 | issue = 1 | pages = 1–17 | year = 2008 | pmid = 4838227 | doi = 10.3109/15563657408987971 }}</ref> Possible effects that can last at least up to two–three years after exposure include blurred vision, [[Fatigue (medical)|tiredness]], declined memory, hoarse voice, [[palpitations]], [[Insomnia|sleeplessness]], shoulder stiffness and [[eye strain]]. In people exposed to nerve agents, [[Serum (blood)|serum]] and [[Red blood cell|erythrocyte]] acetylcholinesterase in the long-term are noticeably lower than normal and tend to be lower the worse the persisting symptoms are.<ref name=pmid11713003>{{cite journal | vauthors = Nishiwaki Y, Maekawa K, Ogawa Y, Asukai N, Minami M, Omae K | title = Effects of Sarin on the nervous system in rescue team staff members and police officers 3 years after the Tokyo subway Sarin attack | journal = Environmental Health Perspectives | volume = 109 | issue = 11 | pages = 1169–73 | date = November 2001 | pmid = 11713003 | pmc = 1240479 | author7 = Sarin Health Effects Study Group | doi=10.1289/ehp.011091169}}</ref><ref name=pmid10616267>{{cite journal | vauthors = Nakajima T, Ohta S, Fukushima Y, Yanagisawa N | title = Sequelae of Sarin toxicity at one and three years after exposure in Matsumoto, Japan | journal = Journal of Epidemiology | volume = 9 | issue = 5 | pages = 337–43 | date = November 1999 | pmid = 10616267 | doi = 10.2188/jea.9.337 | doi-access = free }}</ref>

===Mechanism of action===
When a normally functioning [[motor nerve]] is stimulated, it releases the [[neurotransmitter]] [[acetylcholine]], which transmits the impulse to a muscle or organ. Once the impulse is sent, the enzyme [[acetylcholinesterase]] immediately breaks down the acetylcholine in order to allow the muscle or organ to relax.

Nerve agents disrupt the nervous system by inhibiting the function of the enzyme acetylcholinesterase by forming a [[covalent bond]] with its [[active site]], where acetylcholine would normally be broken down (undergo [[hydrolysis]]). Acetylcholine thus builds up and continues to act so that any nerve impulses are continually transmitted and muscle contractions do not stop. This same action also occurs at the gland and organ levels, resulting in uncontrolled drooling, tearing of the eyes (lacrimation) and excess production of mucus from the nose (rhinorrhea).

The reaction product of the most important nerve agents, including Soman, Sarin, Tabun and VX, with acetylcholinesterase were solved by the U.S. Army using [[X-ray crystallography]] in the 1990s.<ref name=pmid10353814>{{cite journal | vauthors = Millard CB, Kryger G, Ordentlich A, Greenblatt HM, Harel M, Raves ML, Segall Y, Barak D, Shafferman A, Silman I, Sussman JL | title = Crystal structures of aged phosphonylated acetylcholinesterase: nerve agent reaction products at the atomic level | journal = Biochemistry | volume = 38 | issue = 22 | pages = 7032–9 | date = June 1999 | pmid = 10353814 | doi = 10.1021/bi982678l }}</ref><ref name="Millard et al 1999">{{cite journal |doi=10.1021/ja992704i |title=Reaction Products of Acetylcholinesterase and VX Reveal a Mobile Histidine in the Catalytic Triad |journal=Journal of the American Chemical Society |volume=121 |issue=42 |pages=9883–4 |year=1999 |last1=Millard |first1=Charles B |last2=Koellner |first2=Gertraud |last3=Ordentlich |first3=Arie |last4=Shafferman |first4=Avigdor |last5=Silman |first5=Israel |last6=Sussman |first6=Joel L | name-list-style = vanc }}</ref> The reaction products have been confirmed subsequently using different sources of acetylcholinesterase and the closely related target enzyme, butyrylcholinesterase. The X-ray structures clarify important aspects of the reaction mechanism (e.g., stereochemical inversion) at atomic resolution and provide a key tool for antidote development.

===Treatment===
Standard treatment for nerve agent [[Organophosphate poisoning|poisoning]] is a combination of an [[anticholinergic]] to manage the symptoms, and an [[oxime]] as an antidote.<ref>{{cite news |last1=Scutti |first1=Susan |title=Treatment for the Soviet-era nerve gas Novichok |url=https://www.cnn.com/2018/07/05/health/treating-patients-poisoned-with-novichok/index.html |work=CNN |date=5 July 2018 }}</ref> Anticholinergics treat the symptoms by reducing the effects of acetylcholine, while oximes displaces phosphate molecules from the [[active site]] of the [[cholinesterase]] enzymes, allowing the breakdown of acetylcholine. Military personnel are issued the combination in an [[autoinjector]] (e.g. [[ATNAA]]), for ease of use in stressful conditions.<ref name=":4">{{Cite web|date=17 January 2002|title=ATNAA Factsheet|url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21175_Atnaa_prntlbl.pdf|access-date=27 July 2020|website=FDA}}</ref>

[[Atropine]] is the standard anticholinergic drug used to manage the symptoms of nerve agent poisoning.<ref name=":1">{{Cite web|url=https://fas.org/nuke/guide/usa/doctrine/army/mmcch/NervAgnt.htm|title=NERVE AGENTS|date=2018-03-08|website=fas.org|archive-url=https://web.archive.org/web/20171212112437/https://fas.org/nuke/guide/usa/doctrine/army/mmcch/NervAgnt.htm|archive-date=2017-12-12}}</ref> It acts as an antagonist to [[muscarinic acetylcholine receptor]]s, blocking the effects of excess acetylcholine.<ref name=":4" /> Some synthetic anticholinergics, such as [[biperiden]],<ref name="pmid10877003">{{cite journal | vauthors = Shih TM, McDonough JH | title = Efficacy of biperiden and atropine as anticonvulsant treatment for organophosphorus nerve agent intoxication | journal = Archives of Toxicology | volume = 74 | issue = 3 | pages = 165–72 | date = May 2000 | pmid = 10877003 | doi=10.1007/s002040050670| s2cid = 13749842 }}</ref> may counteract the central symptoms of nerve agent poisoning more effectively than atropine, since they pass the [[blood–brain barrier]] better.<ref>{{cite journal |last1=Shih |first1=T.-M. |last2=McDonough |first2=J. H. |title=Efficacy of biperiden and atropine as anticonvulsant treatment for organophosphorus nerve agent intoxication |journal=Archives of Toxicology |date=19 May 2000 |volume=74 |issue=3 |pages=165–172 |id={{DTIC|ADA385192}} |doi=10.1007/s002040050670 |pmid=10877003 }}</ref> While these drugs will save the life of a person affected by nerve agents, that person may be incapacitated briefly or for an extended period, depending on the extent of exposure. The endpoint of atropine administration is the clearing of bronchial secretions.<ref name=":1" />

[[Pralidoxime chloride]] (also known as ''2-PAMCl'') is the standard oxime used to treat nerve agent poisoning.<ref name=":1" /> Rather than counteracting the initial effects of the nerve agent on the nervous system as does atropine, pralidoxime chloride reactivates the poisoned enzyme (acetylcholinesterase) by scavenging the phosphoryl group attached on the functional hydroxyl group of the enzyme, counteracting the nerve agent itself.<ref name="pmid11978898">{{cite journal | vauthors = Eddleston M, Szinicz L, Eyer P, Buckley N | title = Oximes in acute organophosphorus pesticide poisoning: a systematic review of clinical trials | journal = QJM | volume = 95 | issue = 5 | pages = 275–83 | date = May 2002 | pmid = 11978898 | pmc = 1475922 | doi=10.1093/qjmed/95.5.275}}</ref> Revival of acetylcholinesterase with pralidoxime chloride works more effectively on [[nicotinic receptors]] while blocking acetylcholine receptors with atropine is more effective on [[muscarinic receptors]].<ref name=":1" />

[[Anticonvulsant]]s, such as diazepam, may be administered to manage seizures, improving long term prognosis and reducing risk of brain damage.<ref name=":1" /> This is not usually self-administered as its use is for actively seizing patients.<ref>{{Cite web|title=Nerve Agent Treatment – Autoinjector Instructions – CHEMM|url=https://chemm.nlm.nih.gov/antidote_nerveagents.htm|access-date=2020-07-27|website=chemm.nlm.nih.gov|language=en}}</ref>

===Countermeasures===
[[Pyridostigmine|Pyridostigmine bromide]] was used by the [[United States Armed Forces|US military]] in the [[Gulf War|first Gulf War]] as a pretreatment for [[Soman]] as it increased the [[median lethal dose]]. It is only effective if taken prior to exposure and in conjunction with Atropine and Pralidoxime, issued in the [[Mark I NAAK]] autoinjector, and is ineffective against other nerve agents. While it reduces fatality rates, there is an increased risk of brain damage; this can be mitigated by administration of an anticonvulsant.<ref>{{Cite web|date=2018-09-03|title=NERVE AGENTS|url=https://fas.org/nuke/guide/usa/doctrine/army/mmcch/NervAgnt.htm|access-date=2020-07-27|archive-url=https://web.archive.org/web/20180903235711/https://fas.org/nuke/guide/usa/doctrine/army/mmcch/NervAgnt.htm|archive-date=2018-09-03}}</ref> Evidence suggests that the use of pyridostigmine may be responsible for some of the symptoms of [[Gulf War syndrome]].<ref>{{Cite journal|last=Golomb|first=Beatrice Alexandra|date=2008-03-18|title=Acetylcholinesterase inhibitors and Gulf War illnesses|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=105|issue=11|pages=4295–4300|doi=10.1073/pnas.0711986105|issn=0027-8424|pmc=2393741|pmid=18332428|bibcode=2008PNAS..105.4295G|doi-access=free}}</ref>

[[Butyrylcholinesterase]] is under development by the U.S. Department of Defense as a [[prophylactic]] [[countermeasure]] against [[organophosphate]] nerve agents. It binds nerve agent in the bloodstream before the poison can exert effects in the nervous system.<ref name=pmid25448037>{{cite journal | vauthors = Lockridge O | title = Review of human butyrylcholinesterase structure, function, genetic variants, history of use in the clinic, and potential therapeutic uses | journal = Pharmacology & Therapeutics | volume = 148 | pages = 34–46 | date = April 2015 | pmid = 25448037 | doi = 10.1016/j.pharmthera.2014.11.011 }}</ref>

Both purified [[acetylcholinesterase]] and butyrylcholinesterase have demonstrated success in animal studies as "biological scavengers" (and universal targets) to provide [[stoichiometry|stoichiometric]] protection against the entire spectrum of organophosphate nerve agents.<ref name=pmid1986743>{{cite journal | vauthors = Ashani Y, Shapira S, Levy D, Wolfe AD, Doctor BP, Raveh L | title = Butyrylcholinesterase and acetylcholinesterase prophylaxis against Soman poisoning in mice | journal = Biochemical Pharmacology | volume = 41 | issue = 1 | pages = 37–41 | date = January 1991 | pmid = 1986743 | doi = 10.1016/0006-2952(91)90008-S }}</ref><ref name=pmid8343986>{{cite journal | vauthors = Doctor BP, Blick DW, Caranto G, Castro CA, Gentry MK, Larrison R, Maxwell DM, Murphy MR, Schutz M, Waibel K | title = Cholinesterases as scavengers for organophosphorus compounds: protection of primate performance against Soman toxicity | journal = Chemico-Biological Interactions | volume = 87 | issue = 1–3 | pages = 285–93 | date = June 1993 | pmid = 8343986 | doi = 10.1016/0009-2797(93)90056-5 | bibcode = 1993CBI....87..285D }}</ref> Butyrylcholinesterase currently is the preferred enzyme for development as a pharmaceutical drug primarily because it is a naturally circulating human plasma protein (superior [[pharmacokinetics]]) and its larger active site compared with acetylcholinesterase may permit greater flexibility for future design and improvement of butyrylcholinesterase to act as a nerve agent scavenger.<ref name=pmid10421478>{{cite journal | vauthors = Broomfield CA, Lockridge O, Millard CB | title = Protein engineering of a human enzyme that hydrolyzes V and G nerve agents: design, construction and characterization | journal = Chemico-Biological Interactions | volume = 119–120 | pages = 413–8 | date = May 1999 | pmid = 10421478 | doi = 10.1016/S0009-2797(99)00053-8 | bibcode = 1999CBI...119..413B }}</ref>