CBRNE - Nerve Agents, V-series - Ve, Vg, Vm, Vx 

  • Author: Daniel C Keyes, MD, MPH; Chief Editor: Robert G Darling, MD, FACEP   more...
 
Updated: Mar 16, 2010
 

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 NameChemical Name
VXO-Ethyl-S-[2(diisopropylamino)ethyl] methylphosphonothioate
VEO-Ethyl-S-[2-(diethylamino)ethyl] ethylphosphonothioate
VGO,O-Diethyl-S-[2-(diethylamino)ethyl] phosphorothioate
VMO-Ethyl-S-[2-(diethylamino)ethyl] methylphosphonothioate
V-gasRussian equivalent of VX
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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).

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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

(Open Table in a new window)

AgentLCt50 (mg·min/m3)LD50 (mg)Aging Half-Life
Tabun (GA)400100046 h
Sarin (GB)10017005.2-12 h
Soman (GD)5010040 sec to 10 min
VX101050-60 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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Contributor Information and Disclosures
Author

Daniel C Keyes, MD, MPH  Vice Chair, Academic Affairs, Department of Emergency Medicine, John Peter Smith Health Network; Clinical Associate Professor, Department of Surgery, Division of Emergency Medicine and Toxicology, University of Texas Southwestern School of Medicine

Daniel C Keyes, MD, MPH is a member of the following medical societies: American College of Emergency Physicians, American College of Medical Toxicology, American College of Occupational and Environmental Medicine, and American College of Physicians-American Society of Internal Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

Fernando L Benitez, MD  Assistant Medical Director, Dallas Metropolitan BioTel (EMS) System; Associate Professor in Emergency Medicine, Department of Surgery, Division of Emergency Medicine, University of Texas Southwestern Medical Center and Parkland Health and Hospital

Fernando L Benitez, MD is a member of the following medical societies: American College of Emergency Physicians, American Medical Association, and National Association of EMS Physicians

Disclosure: Nothing to disclose.

Larissa I Velez-Daubon, MD  Associate Professor, Associate Program Director, Department of Surgery, Division of Emergency Medicine, University of Texas Southwestern Medical School, Parkland Memorial Hospital; Associate Program Director and Staff Toxicologist, Department of Surgery, Division of Emergency Medicine, North Texas Poison Center, Parkland Memorial Hospital

Larissa I Velez-Daubon, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Emergency Physicians, American College of Medical Toxicology, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Specialty Editor Board

Fred Henretig, MD  Director, Section of Clinical Toxicology, Professor, Medical Director, Delaware Valley Regional Poison Control Center, Departments of Emergency Medicine and Pediatrics, University of Pennsylvania School of Medicine, Children's Hospital

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD  Senior Pharmacy Editor, eMedicine

Disclosure: eMedicine Salary Employment

Rick Kulkarni, MD 

Rick Kulkarni, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American College of Emergency Physicians, American Medical Association, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine

Disclosure: WebMD Salary Employment

John D Halamka, MD, MS  Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center

John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Chief Editor

Robert G Darling, MD, FACEP  Adjunct Clinical Assistant Professor of Military and Emergency Medicine, Uniformed Services University of the Health Sciences, F Edward Hebert School of Medicine; Associate Director, Center for Disaster and Humanitarian Assistance Medicine

Robert G Darling, MD, FACEP is a member of the following medical societies: American College of Emergency Physicians, American Medical Association, American Telemedicine Association, and Association of Military Surgeons of the US

Disclosure: Nothing to disclose.

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Chemical Terrorism Agents and Syndromes. Signs and symptoms. Chart courtesy of North Carolina Statewide Program for Infection Control and Epidemiology (SPICE), copyright University of North Carolina at Chapel Hill, www.unc.edu/depts/spice/chemical.html.
Table 1. Code and Chemical Names for the V-Series Agents
Code NameChemical Name
VXO-Ethyl-S-[2(diisopropylamino)ethyl] methylphosphonothioate
VEO-Ethyl-S-[2-(diethylamino)ethyl] ethylphosphonothioate
VGO,O-Diethyl-S-[2-(diethylamino)ethyl] phosphorothioate
VMO-Ethyl-S-[2-(diethylamino)ethyl] methylphosphonothioate
V-gasRussian equivalent of VX
Table 2
AgentLCt50 (mg·min/m3)LD50 (mg)Aging Half-Life
Tabun (GA)400100046 h
Sarin (GB)10017005.2-12 h
Soman (GD)5010040 sec to 10 min
VX101050-60 h
Table 3. Pharmacologic Effects of Nerve Agents*
Receptor InvolvedClinical 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]
Table 4. Severity of Toxicity from Liquid and Vapor Exposures
Severity of ExposureSigns and Symptoms - LiquidSigns and Symptoms - Vapor
Onset of symptomsPossibly delayed toxicityRapidly manifesting toxicity
MinimalLocalized sweating at site



Localized fasciculations at site



Miosis



Rhinorrhea



Mild dyspnea



ModerateFasciculations



Diaphoresis



Nausea, vomiting, and diarrhea



Generalized weakness



Above symptoms and the following:



Moderate-to-marked dyspnea (bronchorrhea and/or bronchoconstriction)



SevereAbove 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



Table 5. Drugs Used to Treat Nerve Agent–Poisoned Patients*
DrugDoseRouteIndicationsContraindications
Atropine2 mg q5-10min prn



Note: the Mark 1 kit contains 2 mg of atropine



IV/IM/ETTExcessive muscarinic symptomsRelative - 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/IMSymptomatic nerve agent poisoningRapid infusion may result in hypertension
Diazepam (Valium)2-5 mg IV or 10 mg IMIV/IMActive seizures; administer as prophylaxis if moderate or severe signs of poisoning are presentNone
*Adapted from Sidell.
Table 6. Summary of Treatment Modalities According to Severity of Exposure*
Severity/Route of ExposureAtropine2-PAM ClDiazepamOther
SuspectedNoNoNoDecontamination and 18-h observation for liquid exposures
Mild2 mg for severe rhinorrhea or dyspnea; may repeat prnAdminister if patient has nonimproving dyspnea or GI symptomsNoDecontamination and 18-h observation for liquid exposures; oxygen
Moderate6 mg; may require repeat dosesAdminister with atropineAdminister even in absence of seizuresDecontamination, oxygen
SevereStart with 6 mg; may need to repeatAdminister with atropine; should repeat once or twiceAdminister even in absence of seizuresABCs, decontamination
*Adapted from Sidell.
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