Background
Nerve agents are compounds that have the capacity to inactivate the enzyme acetylcholinesterase (AChE). [1, 2] The first compounds to be synthesized were known as the G-series agents ("G" stands for German): tabun (GA), sarin (GB), and soman (GD). [3] These compounds were discovered and synthesized by German scientists, led by Dr Gerhard Schrader, prior to and during World War II.
In 1954, the British first synthesized O-ethyl S-(2-diisopropylaminoethyl) methylphosphonothioate, the most important agent in the V series and coded in the United States as "VX". The V-series weapons, including VX, are among the most highly toxic chemical warfare nerve agents ("V" stands for venomous). The V agents are approximately 10-fold more poisonous than sarin (GB).
The V-series 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 due to low volatility characteristics. 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 other agents in the V series are less known, and the information available about their characteristics is fairly limited in the open, unclassified literature. The other agents also have coded names, including VE, V-gas, VG, and VM (see Table 1 below). This article discusses VX as the prototype of the V-series nerve agents. Table 1. Code and Chemical Names for the V-Series Agents
Table. (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-series 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-series 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, and 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. [4]
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 intentional nerve agent poisoning have been reported in the United States. The However, these agents are still present in certain chemical weapons elimination sites on military facilities. Personnel in these facilities could come in contact with these agents in case of an accidental release. The US produced approximately 4400 tons of VX between 1961 and 1969; it began destruction of its VX stores in 1969 but has not yet completed destruction at all storage sites. [5]
International
No confirmed reports exist of the use of V-series nerve agents in chemical warfare. It is possible that VX or other nerve agents were used by the Iraqis in the 1981-1987 Iran-Iraq War. [6] In February 2017, Kim Jong-nam, the older, estranged brother of Kim Jong-un, the North Korean leader, was killed in the Kuala Lumpur (Malaysia) airport. Two women rubbed chemicals onto his face in very rapid succession. Within 20 minutes, he suffered from what was described as seizures, followed by death. VX was detected in forensic analysis. [7, 8]
The Chemical Weapons Convention (CWC) took effect in 1997 and bans the production, stockpiling, and use of chemical weapons, including VX. [9] 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 two 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). With an LCt50 of 10 mg ⋅ min/m3, VX is the most toxic of the G and V-series 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-series agents are more volaitle, and in addition to penetrating the skin, they are a significant inhalational hazard. Table 2. Toxicity and Half-Lives of Nerve Agents
Table. (Open Table in a new window)
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 |
Tables
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. [10] |
|
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. |
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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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