Nerve agent
Nerve agents, sometimes also called nerve gases, are a class of organic chemicals that disrupt the mechanisms by which nerves transfer messages to organs. The disruption is caused by the blocking of acetylcholinesterase, an enzyme that catalyzes the breakdown of acetylcholine, a neurotransmitter. Nerve agents are irreversible acetylcholinesterase inhibitors used as poison.
Poisoning by a nerve agent leads to constriction of pupils, profuse salivation, convulsions, and involuntary urination and defecation, with the first symptoms appearing in seconds after exposure. Death by asphyxiation or cardiac arrest may follow in minutes due to the loss of the body's control over respiratory and other muscles. Standard treatment for nerve agent poisoning is a combination of an anticholinergic to manage the symptoms, and an oxime as an antidote.
The most mass-produced nerve agents in history are VX/VR, sarin, and soman. The G-series consists of the earliest nerve agents discovered from the late 1930s, which are typically volatile and dangerous via inhalation as aerosols. The V-series, discovered after the 1950s, are far less volatile and more persistent, and threaten via skin absorption, requiring a full body suit. Both series, and some Novichok-series compounds, are organophosphate compounds, while other Novichok agents, and some carbamate nerve agents, have non-organophosphate chemistry. Some are formed by binary chemical weapon munitions, such as the US M687 artillery shell which formed sarin by mixing its chemical precursors.
The first nerve agents were discovered by IG Farben in Nazi Germany. The extreme toxicity of tabun was learned in 1936, followed by sarin in 1938 and soman in 1944. The Wehrmacht became the first military to stockpile nerve agent munitions, but they were not used for fear of Allied retaliation. France, the Soviet Union, the United Kingdom, and the United States all captured and studied German nerve munitions. During the Cold War, the Soviet and United States chemical weapons program became the first and second largest in history, primarily stockpiling thousands of tons nerve agents alongside mustard gas.
Ba'athist Iraq also developed nerve agents, becoming the first country to use them in warfare, killing tens of thousands of civilians and troops in the Iran–Iraq War. This began with a tabun attack in 1984 and included the Halabja massacre, which killed over 3,000 people. The Japanese doomsday cult Aum Shinrikyo was the first to use nerve agents for chemical terrorism, killing dozens in the 1994 Matsumoto sarin attack, 1995 Tokyo subway sarin attack, and assassination attempts with VX-filled syringes. Ba'athist Syria's also used sarin in the Syrian civil war, including the 2013 Ghouta attack, which killed between three hundred and seventeen hundred people.
Nerve agent development, production, and stockpiling were first comprehensively banned by the 1993 Chemical Weapons Convention, adopted by 193 states as of 2026. Despite this, nerve agents were used in the assassination of Kim Jong-nam and poisoning of Sergei and Yulia Skripal, allegedly ordered by North Korea and Russia respectively.
Nerve agents are generally colorless liquids under normal conditions; the popular term "nerve gas" is inaccurate. Agents sarin and VX are odorless; tabun has a slightly fruity odor and soman has a slight camphor odor.
Biological effects
Nerve agents attack the nervous system. All such agents function the same way resulting in cholinergic crisis: they inhibit the enzyme acetylcholinesterase, which is responsible for the breakdown of acetylcholine in the synapses 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. 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 asphyxiation or cardiac arrest in a few minutes, depending upon the dose received and the agent used.Initial symptoms following exposure to nerve agents are a runny nose, tightness in the chest, and 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, lacrimation, urination, defecation,
gastrointestinal pain and vomiting will be experienced. Blisters and burning of the eyes and/or lungs may also occur. This phase is followed by initially myoclonic 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 diaphragm.
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. Possible effects that can last at least up to two–three years after exposure include blurred vision, tiredness, declined memory, hoarse voice, palpitations, sleeplessness, shoulder stiffness and eye strain. In people exposed to nerve agents, serum and erythrocyte acetylcholinesterase in the long-term are noticeably lower than normal and tend to be lower the worse the persisting symptoms are.
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. 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 and excess production of mucus from the nose.
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. 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 at atomic resolution and provide a key tool for antidote development.
Treatment
Standard treatment for nerve agent poisoning is a combination of an anticholinergic to manage the symptoms, and an oxime as an antidote. 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, for ease of use in stressful conditions.Atropine is the standard anticholinergic drug used to manage the symptoms of nerve agent poisoning. It acts as an antagonist to muscarinic acetylcholine receptors, blocking the effects of excess acetylcholine. Some synthetic anticholinergics, such as biperiden, may counteract the central symptoms of nerve agent poisoning more effectively than atropine, since they pass the blood–brain barrier better. 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.
Pralidoxime chloride is the standard oxime used to treat nerve agent poisoning. Rather than counteracting the initial effects of the nerve agent on the nervous system as does atropine, pralidoxime chloride reactivates the poisoned enzyme by scavenging the phosphoryl group attached on the functional hydroxyl group of the enzyme, counteracting the nerve agent itself. Revival of acetylcholinesterase with pralidoxime chloride works more effectively on nicotinic receptors while blocking acetylcholine receptors with atropine is more effective on muscarinic receptors.
Anticonvulsants, such as diazepam, may be administered to manage seizures, improving long term prognosis and reducing risk of brain damage. This is not usually self-administered as its use is for actively seizing patients.
Countermeasures
was used by the US military in the 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. Evidence suggests that the use of pyridostigmine may be responsible for some of the symptoms of Gulf War syndrome.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.
Both purified acetylcholinesterase and butyrylcholinesterase have demonstrated success in animal studies as "biological scavengers" to provide stoichiometric protection against the entire spectrum of organophosphate nerve agents. Butyrylcholinesterase currently is the preferred enzyme for development as a pharmaceutical drug primarily because it is a naturally circulating human plasma protein 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.