CBRNE - Nerve Agents, V-series - Ve, Vg, Vm, Vx
- Author: Daniel C Keyes, MD, MPH; Chief Editor: Robert G Darling, MD, FACEP more...
Background
The V-series weapons, including VX, are the most highly toxic chemical warfare nerve agents. Nerve agents are compounds that have the capacity to inactivate the enzyme acetylcholinesterase (AChE). The first compounds to be synthesized were known as the G agents ("G" stands for German): tabun (GA), sarin (GB), and soman (GD). These compounds were discovered and synthesized by German scientists, led by Dr Gerhard Schrader, during World War II.
The V agents are part of the group of persistent agents, which are nerve agents that can remain on skin, clothes, and other surfaces for long periods of time. The consistency of these agents is similar to oil; thus, the inhalation hazard is less than with the G agents. This consistency thus renders them toxic mainly by dermal exposures. The British first synthesized O-ethyl S-(2-diisopropylaminoethyl) methylphosphonothioate (VX) in 1954. The most important agent in the series was coded in the US as VX. The other agents in the series are less known, and the information available about them is fairly limited. The other agents also have coded names, including VE, V-gas, VG, and VM (see Table 1 below). The V agents are approximately 10-fold more poisonous than sarin (GB). Since many of the agents in this series have not been studied extensively, this article discusses VX as the prototype of the series.
Table 1. Code and Chemical Names for the V-Series Agents (Open Table in a new window)
| Code Name | Chemical Name |
| VX | O-Ethyl-S-[2(diisopropylamino)ethyl] methylphosphonothioate |
| VE | O-Ethyl-S-[2-(diethylamino)ethyl] ethylphosphonothioate |
| VG | O,O-Diethyl-S-[2-(diethylamino)ethyl] phosphorothioate |
| VM | O-Ethyl-S-[2-(diethylamino)ethyl] methylphosphonothioate |
| V-gas | Russian equivalent of VX |
Pathophysiology
The V agents bind to AChE much more potently than the organophosphate and carbamate insecticides. AChE is the enzyme that mediates the degradation of acetylcholine (ACh). ACh is an important neurotransmitter of the peripheral nervous system. It activates 2 types of receptors, muscarinic and nicotinic. Nicotinic ACh receptors are found at the skeletal muscle and at the preganglionic autonomic fibers. Muscarinic ACh receptors are found mainly in the postganglionic parasympathetic fibers. In addition, ACh is believed to mediate neurotransmission in the central nervous system (CNS).
ACh is released when an electrical impulse reaches the presynaptic neuron. It travels in the synaptic cleft and reaches the postsynaptic membrane, where it binds to its receptor (muscarinic or nicotinic). This activates the ACh receptor and results in a new action potential, transmitting the signal down the neuron. Normally, after this interaction between ACh and its receptor, ACh detaches from its receptor and is degraded (hydrolyzed) into choline and acetic acid by AChE. This regenerates the receptor and renders it active again. The choline moiety undergoes reuptake into the presynaptic cell and is recycled to produce ACh.
Nerve agents act by inhibiting the hydrolysis of ACh by AChE. Nerve agents bind to the active site of AChE, rendering it incapable of deactivating ACh. Any ACh that is not hydrolyzed still can interact with the receptor, resulting in persistent and uncontrolled stimulation of that receptor. After persistent activation of the receptor, fatigue occurs. This is the same principle used by the depolarizing neuromuscular blocker succinylcholine. Thus, the clinical effects of nerve agent poisoning are the result of this persistent stimulation and subsequent fatigue at the muscarinic and nicotinic ACh receptors.
"Aging" and VX nerve agent
For all nerve agents, including the V agents, inactivation of AChE eventually becomes permanent (irreversible). This phenomenon of irreversible inactivation of AChE is known as aging. Aging represents the formation of a covalent bond between the nerve agent and the AChE. Once aging occurs, the AChE enzyme cannot be reactivated. After aging occurs, new AChE must be produced in order for the clinical effect of the nerve agent to be reversed. This new enzyme production is a very slow process. This irreversible binding is one important difference between organophosphate compounds (including nerve agents) and carbamates. For carbamates, AChE binding is always reversible. With VX, a small degree of spontaneous enzyme reactivation occurs, which has been found to be approximately 6% per day for the first 3-4 days and then 1% per day.
The amount of time (listed as aging half-life) required for aging by various nerve agents is listed in Table 2 in Mortality/Morbidity. The nerve agent VX has a very long aging half-life of more than 2 days. This means that certain antidotes will be effective much longer for this agent than for the others (see Treatment).
Epidemiology
Frequency
United States
No instances of nerve agent poisoning have been reported in the United States. However, these agents are still present in certain military facilities. Military personnel in these facilities could come in contact with these agents in case of an accidental release.
International
Although G agents were synthesized during World War II, no evidence exists that they ever were actually deployed during this conflict. They were tested in concentration camps but not in the battlefield. The only confirmed wartime use of nerve agents was during the 1981-1987 Iran-Iraq War, where tabun and sarin were used by Iraq in an effort to gain advantage over Iran. Current literature does not indicate whether VX was used by the Iraqis, although they were found to have substantial stockpiles of the agent at the time of the first Gulf War. They were also reported to have used them against various Kurdish civilians in the north of Iraq.
The Chemical Weapons Convention (CWC) took effect in 1997 and bans the production, stockpiling, and use of chemical weapons. It also provides for the monitoring of their destruction through the Organisation for the Prohibition of Chemical Weapons.
Mortality/Morbidity
Toxicity of nerve agents is typically described in 2 ways: LCt50 and LD50. LCt50 refers to the inhalational toxicity of the vapor form. "Ct" refers to the concentration of the vapor or aerosol in the air (measured as mg/m3) multiplied by the time the individual is exposed (measured in minutes). At 10 mg·min/m3, VX is the most toxic of the nerve agents (see Table 2). VX also is the least volatile of the nerve agents, which renders it hazardous mainly by the percutaneous and dermal routes. By contrast, G agents tend to volatilize instead of penetrating the skin, which makes them a significant inhalational hazard. Table 2. Toxicity and Half-Lives of Nerve Agents
| Agent | LCt50 (mg·min/m3) | LD50 (mg) | Aging Half-Life |
| Tabun (GA) | 400 | 1000 | 46 h |
| Sarin (GB) | 100 | 1700 | 5.2-12 h |
| Soman (GD) | 50 | 100 | 40 sec to 10 min |
| VX | 10 | 10 | 50-60 h |
Race
Sensitivity to nerve agents varies with the individual, but no studies have addressed this differential in susceptibility.
Sex
No evidence exists of any differential susceptibility between the sexes.
Age
No evidence exists of a differential susceptibility based on age.
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- Table 1. Code and Chemical Names for the V-Series Agents
- Table 2
- Table 3. Pharmacologic Effects of Nerve Agents*
- Table 4. Severity of Toxicity from Liquid and Vapor Exposures
- Table 5. Drugs Used to Treat Nerve Agent–Poisoned Patients*
- Table 6. Summary of Treatment Modalities According to Severity of Exposure*
| Code Name | Chemical Name |
| VX | O-Ethyl-S-[2(diisopropylamino)ethyl] methylphosphonothioate |
| VE | O-Ethyl-S-[2-(diethylamino)ethyl] ethylphosphonothioate |
| VG | O,O-Diethyl-S-[2-(diethylamino)ethyl] phosphorothioate |
| VM | O-Ethyl-S-[2-(diethylamino)ethyl] methylphosphonothioate |
| V-gas | Russian equivalent of VX |
| Agent | LCt50 (mg·min/m3) | LD50 (mg) | Aging Half-Life |
| Tabun (GA) | 400 | 1000 | 46 h |
| Sarin (GB) | 100 | 1700 | 5.2-12 h |
| Soman (GD) | 50 | 100 | 40 sec to 10 min |
| VX | 10 | 10 | 50-60 h |
| Receptor Involved | Clinical Effect |
| Acetylcholine, GABA, N -methyl-D -aspartate: Central (CNS) | Anxiety, restlessness, seizures, failure to concentrate, depression, coma, apnea |
| Acetylcholine: Muscarinic Postganglionic parasympathetic | "DUMBELS" (commonly used mnemonic) D - Diarrhea U - Urination M - Miosis B - Bronchorrhea, bronchoconstriction E - Emesis L - Lacrimation S - Salivation Note: The other commonly used mnemonic "SLUDGE" is not used here, as it does not include an important sign and symptom: bronchorrhea and bronchoconstriction. |
| Acetylcholine: Nicotinic Motor endplate Sympathetic and parasympathetic ganglia | Pallor, tachycardia, hypertension, muscle weakness and/or paralysis, fasciculations Note: Some use the days of the week as an easy mnemonic for these: M - Mydriasis T - Tachycardia W - Weakness tH - Hypertension F - Fasciculations |
| * Adapted from Marrs, Maynard, and Sidell.[1] | |
| Severity of Exposure | Signs and Symptoms - Liquid | Signs and Symptoms - Vapor |
| Onset of symptoms | Possibly delayed toxicity | Rapidly manifesting toxicity |
| Minimal | Localized sweating at site Localized fasciculations at site | Miosis Rhinorrhea Mild dyspnea |
| Moderate | Fasciculations Diaphoresis Nausea, vomiting, and diarrhea Generalized weakness | Above symptoms and the following: Moderate-to-marked dyspnea (bronchorrhea and/or bronchoconstriction) |
| Severe | Above symptoms and the following: Loss of consciousness Seizures Generalized fasciculations Flaccid paralysis and apnea | Above symptoms and the following: Loss of consciousness Seizures Generalized fasciculations Flaccid paralysis and apnea |
| Drug | Dose | Route | Indications | Contraindications |
| Atropine | 2 mg q5-10min prn Note: the Mark 1 kit contains 2 mg of atropine | IV/IM/ETT | Excessive muscarinic symptoms | Relative - IV route in hypoxia has been associated with ventricular fibrillation |
| 2-PAM Cl (pralidoxime chloride, Protopam) | 15-25 mg/kg over 20 min; can be repeated after 1 h Note: The Mark 1 kit contains 600 mg of pralidoxime. | IV/IM | Symptomatic nerve agent poisoning | Rapid infusion may result in hypertension |
| Diazepam (Valium) | 2-5 mg IV or 10 mg IM | IV/IM | Active seizures; administer as prophylaxis if moderate or severe signs of poisoning are present | None |
| *Adapted from Sidell. | ||||
| Severity/Route of Exposure | Atropine | 2-PAM Cl | Diazepam | Other |
| Suspected | No | No | No | Decontamination and 18-h observation for liquid exposures |
| Mild | 2 mg for severe rhinorrhea or dyspnea; may repeat prn | Administer if patient has nonimproving dyspnea or GI symptoms | No | Decontamination and 18-h observation for liquid exposures; oxygen |
| Moderate | 6 mg; may require repeat doses | Administer with atropine | Administer even in absence of seizures | Decontamination, oxygen |
| Severe | Start with 6 mg; may need to repeat | Administer with atropine; should repeat once or twice | Administer even in absence of seizures | ABCs, decontamination |
| *Adapted from Sidell. | ||||
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