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CBRNE - Nerve Agents, V-series - Ve, Vg, Vm, Vx
Updated: Mar 16, 2010
Introduction
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 AgentsOpen table in new window
Table
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 |
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).
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
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Table
| 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 |
| 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.
Clinical
History
- The onset of symptoms after exposure to a V agent varies according to the route and quantity of exposure.
- After inhalation, onset is rapid due to the high vascularity of the lungs and because the lungs are primary target organs. However, it must be remembered that, due to the low volatility of the V agents, this is not the most common route of exposure.
- After cutaneous exposure, systemic symptoms may be delayed for minutes to hours. The V agents may present rapidly if a large exposure occurs. However, clinical manifestations may be delayed for several hours after lesser exposures, as the agent diffuses slowly through the keratin layers of the skin. This is in contrast to the G (volatile) agents, which are expected to cause onset of symptoms in the first few minutes after exposure.
- The onset of symptoms also depends on the area of the skin that is exposed. In sites where the dermal layers are thin (eg, eyelids, ears), penetration by the nerve agent is more rapid.
- In many situations, history of exposure to a nerve agent is absent. In case of a terrorist attack, suspect the diagnosis when multiple patients present with symptoms of cholinergic excess.
- Occupational history may aid in making the diagnosis in cases of accidental releases. Military personnel, chemical demilitarization laborers, and laboratory workers may be at particular risk for exposure.
Physical
Clinical signs and symptoms are related to excessive stimulation at the nicotinic and muscarinic cholinergic receptors. Central effects may be mediated by cholinergic receptors, as well as by effects on N -methyl-D -aspartate-ergic and GABA-ergic systems. See Table 3 for a summary of the clinical effects of nerve agents.
Table 3. Pharmacologic Effects of Nerve Agents*
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Table
Receptor Involved | Clinical Effect |
Acetylcholine, GABA, N -methyl-D -aspartate: Central (CNS) | Anxiety, restlessness, seizures, failure to concentrate, depression, coma, apnea |
Acetylcholine: Muscarinic
| "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
| Pallor, tachycardia, hypertension, muscle weakness and/or paralysis, fasciculations |
Receptor Involved | Clinical Effect |
Acetylcholine, GABA, N -methyl-D -aspartate: Central (CNS) | Anxiety, restlessness, seizures, failure to concentrate, depression, coma, apnea |
Acetylcholine: Muscarinic
| "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
| Pallor, tachycardia, hypertension, muscle weakness and/or paralysis, fasciculations |
* Adapted from Marrs, Maynard, and Sidell.1
- Eyes
- The most common effects of nerve agents on the eyes are conjunctival injection and pupillary constriction, known as miosis. The patient complains of eye pain, dim vision, and blurred vision. This is most likely from direct contact between the agent and eye.
- Miosis may persist for long periods and may be unilateral. Severe miosis results in the complaint of dim vision. Ciliary spasm also may cause eye pain.
- Patients exposed to VX may not have miosis. This is most likely because the eye usually is not exposed directly to the agent, unlike with the G agents. Miosis may be a delayed sign of VX exposure.
- Nose: Rhinorrhea is most common after a vapor exposure but also can be observed with exposures by other routes.
- Lungs
- Shortness of breath is an important complaint. Patients may describe chest tightness, respiratory distress, or gasping and even may present in apnea. Bronchoconstriction and excessive bronchial secretions cause these important life-threatening symptoms.
- With severe exposures, death may result from central respiratory depression and/or complete paralysis of the muscles of respiration. Respiratory failure is the major cause of death in nerve agent poisoning.
- Skeletal muscle: Fasciculations are the most specific identifiable manifestations of intoxication with these agents. Upon initial exposure, they can be localized, but they then spread to cause generalized involvement of the entire musculature (after severe exposures). Myoclonic jerks (twitches) may be observed. Eventually, muscles fatigue and a flaccid paralysis ensues.
- Skin: With small liquid exposures, localized sweating can be observed along with the fasciculations. Generalized diaphoresis can occur with larger exposures.
- Gastrointestinal: Abdominal cramping can be present. With larger exposures, nausea, vomiting, and diarrhea are more prominent.
- Heart
- The patient may present with either bradycardia or tachycardia. Heart rate depends on the predominance of sympathetic stimulation (resulting in tachycardia) or of the parasympathetic tone (causing bradycardia via vagal stimulation). Hypoxemia also increases adrenergic tone, which also manifests itself with tachycardia. Heart rate is thus an unreliable sign of nerve agent poisoning.
- Many disturbances in cardiac rhythm have been reported after both organophosphate and nerve agent poisonings. Heart blocks and premature ventricular contractions can be observed. The 2 arrhythmias of greatest concern are torsade des pointes and ventricular fibrillation.
- Central nervous system
- Smaller exposures to nerve agents may result in behavioral changes such as anxiety, psychomotor depression, intellectual impairment, and unusual dreams.
- Large exposures to nerve agents result in altered mentation, loss of consciousness, and seizures.
- Most signs and symptoms are related to the excessive activation and subsequent fatigue at the cholinergic receptors. Some authors have divided exposures into minimal, moderate, and severe toxicity. Signs and symptoms associated with each exposure are summarized in Table 4.
- Table 4. Severity of Toxicity from Liquid and Vapor Exposures
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[ CLOSE WINDOW ]Table
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 siteMiosis
Rhinorrhea
Mild dyspneaModerate Fasciculations
Diaphoresis
Nausea, vomiting, and diarrhea
Generalized weaknessAbove 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 apneaAbove symptoms and the following:
Loss of consciousness
Seizures
Generalized fasciculations
Flaccid paralysis and apneaSeverity 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 siteMiosis
Rhinorrhea
Mild dyspneaModerate Fasciculations
Diaphoresis
Nausea, vomiting, and diarrhea
Generalized weaknessAbove 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 apneaAbove symptoms and the following:
Loss of consciousness
Seizures
Generalized fasciculations
Flaccid paralysis and apnea
Causes
The nerve agents are not readily available. Suspect nerve agent exposures in military or research laboratory workers who may have access to these substances. Also, suspect nerve agent poisoning when several patients present with signs and symptoms of cholinergic overstimulation. This presentation would be typical during a terrorist event, as seen in the 1995 Tokyo subway attack, in which sarin was released.
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Further Reading
Keywords
persistent agents, G agents, VX, O-ethyl S-(2-diisopropylaminoethyl) methylphosphonothioate, nerve agents, chemical warfare, V-series agents, Vx, Ve, Vg, Vm, V-series weapons, V agents
