Nerve agents

1
Nerve agents

• Ziad Kazzi, MD
• Medical Toxicology Fellow
• Centers for Disease Control and Prevention

2
Introduction

• Nerve agents are aptly named, since they affect
  the nervous system.
• Structural name for these agents is organic
  phosphorous compounds (OPCs)
• Term nerve agents commonly used to refer to a
  specific military class of OPCs
• soman, sarin, tabun, VX

3
Introduction (continued)

• In fact, the OPCs also include several hundred
  nonmilitary OPCs.
• Malathion
• Parathion
• Others
• Used commonly as insecticides, where military
  OPCs are used to kill humans
• Both can kill humans, just differently.

4
Introduction (continued)

• Carbamates have similar mechanism of action. They
  are separate from organophosphates.
• Reversible enzyme binding
• Nerve agents are used in the treatment of
  myasthenia gravis and anticholinergic drug
  poisoning.

5
Background

• Developed in pre-World War II Germany by Gerhardt
  Schrader, who discovered tabun in 1934.
• Germany later developed sarin and soman. These
  are the G agents.
• Never used by the Germans. The British (R. Gosh)
  synthesized VX (the acronym allegedly stands for
  venomous) after WWII.

6
Background (continued)

• Iraq reportedly used tabun and maybe sarin in the
  Iran-Iraq war (19841988).
• Iranian soldiers had atropine auto-injectors.
• Many had atropine overdoses from misuse of their
  auto-injectors.

7
Background (continued)

• Sarin gas was released in the Tokyo subway system
  by the Aum Shinrikyo Cult, creating more than
  5,000 victims and causing 12 deaths.
• The same cult had released sarin in an apartment
  complex in Matsumoto in 1994, killing seven and
  injuring more than 600 people.
• In Tokyo, sarin was concealed in lunch boxes and
  bags. The terrorists punctured the bags with
  umbrellas and ran out of the subway
  tunnel.

8
Background (continued)

• The United States has over 30,000 tons of VX and
  sarin.
• The government is planning the destruction of
  this stock and has already destroyed small
  batches.
• Dupont Chemical is negotiating for the contract
  to destroy 1,200 tons of VX stored in the Newport
  chemical depot.
• There is an ongoing discussion about the best way
  to dispose of the end products.

9
Military Designations

• Tabun GA
• Sarin GB
• Soman GD
• Cyclosarin GF
• VX

10
Physical Properties

• Liquids with varying volatility and persistence
• VX is the least volatile but the most persistent
  oily. Soman is odorless.
• Tabun, sarin, and soman have significant
  volatility. Sarin is the most volatile.
• Absorbed via skin, mucus membranes, lungs, and
  gastrointestinal system.

11
Toxicity

• Dermal toxicity One drop of VX,110 ml of the G
  agents may be fatal.
• Onset of symptoms may be delayed several hours
  from exposure to the liquid form, especially VX
  (up to 18 hours).
• Rapid development of symptoms after exposure is
  more likely.

12
Lethality of VX

• An amount of VX equal in size to one column of
  the building depicted on the back of this penny
  would be lethal.

13
Mechanism of Action

• Nerve agents bind and inhibit acetylcholine
  esterases.
• Acetylcholine esterase breaks down acetylcholine
  (ACh).
• ACh mediates neurotransmission at
• nicotinic muscular junctions,
• autonomic nicotinic synaptic junctions
  (sympathetic and parasympathetic), and
• muscarinic end-organ synapses (GI tract, glands,
  bladder, pupils).

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Autonomic Nervous System Somatic
Central
Parasympathetic Sympathetic
AutonomicGanglia
N
N
N
N
ACh
ACh
ACh
ACh
M
ACh
M
A
A
N
M
End Organ
Brain
ACh
ACh
Epinephrine
Norepinephrine
ACh
Glands Bladder Gut Heart
Heart Blood Pressure
Neuromuscular Junction
Sweat Glands
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Mechanism of Action (continued)

• Enzyme inhibition is reversible within a certain
  period of time that is agent dependent.
• This time period in which structural changes to
  the enzyme occur is called aging.
• Soman ages within minutes, whereas sarin takes
  hours.
• After aging occurs, the enzyme is inactivated.
  Enzyme regeneration usually takes several weeks.
• Excess ACh at all these synapses accounts for the
  clinical presentation.

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Clinical Presentation

• Muscarinic
• SLUDGE BBBs
• Salivation Bradycardia
• Lacrimation Bronchorrhea
• Urination Bronchospasm
• Diaphoresis
• GI distress (diarrhea, vomiting)
• Emesis
• Miosis

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Clinical Presentation (continued)

• Nicotinic MTWThF
• Mydriasis
• Tachycardia
• Weakness
• Hyperthermia
• Fasciculation

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Clinical Presentation (continued)

• Military class OPCs (sarin, soman, etc.)
• Preferential affinity for nicotinic receptors
• Muscle paralysis
• Effective battlefield weapon
• Insecticide class OPCs (malathion)
• Preferential affinity for muscarinic receptors
• SLUDGE
• BBBs

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Clinical Presentation (continued)

• Dim vision and eye pain from ciliary spasm or
  direct cortical effect?
• Cardiovascular effects are less predictable and
  range from bradycardia with AV blocks to
  tachycardia.

20
Clinical Presentation (continued)

• Compared with adults, children exposed to nerve
  agents are thought to be less likely to have
  miosis and more likely to have increased
  secretions.
• Children are also thought to have more seizures,
  hypotonia, and weakness than adults.
• No studies have been done on nerve agents and
  children, even though historical incidents have
  affected children.
• Assumptions about children and nerve agents are
  based on knowledge of organophosphates and of
  characteristics of children such as lower weight,
  less active metabolism (paroxanase activity), and
  greater ventilatory rate.

21
Differential Diagnosis for Nerve Agent Poisoning

• Gastroenteritis
• Ingestion of muscarinic mushrooms (Amanita
  muscaria, Clytocybe, Inocybe)
• Pesticide poisoning
• Carbamate overdose
• Metal ingestion

22
Diagnostic Workup

• No lab workup is useful for acute nerve agent
  poisoning.
• RBC and plasma cholinesterase (butylcholinesterase
  ) levels may be checked. These results are
  usually not immediately available.

23
Prehospital Care and Decontamination

• First responders Respirators, goggles,
  protective clothing
• Self-contained breathing apparatus (SCBA) is
  recommended in response to any nerve agent vapor
  or liquid.
• Butyl rubber gloves (most agents are lipophilic)
• 20 of healthcare workers in Tokyo had mild
  symptoms after taking care of patients. These
  symptoms included nausea, eye pain, and headache.

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Prehospital Care and Decontamination (continued)

• Inhalation exposure removal from exposure
• Dermal wash with soap and water or mild (0.5)
  sodium hypochlorite (bleach) solution if
  availability of water is limited
• Ingestion no charcoal as these patients are at
  risk for vomiting and aspiration

25
Antidotes Atropine

• Muscarinic receptor antagonist.
• Only treats muscarinic symptoms.
• Given IV, IM, or by ET tube.
• Dose is 2 mg every 510 minutes. End point is
  resolution of bronchorrhea.
• For children, give 0.51.0 mg IM/IV every 520
  minutes. For children lt 6 months old, the dose is
  0.05 mg/kg, with the minimum dose being 0.1 mg.
  Same end point.
• If given early, atropine may prevent seizures.
• Glycopyrrolate may also be used but does not
  penetrate the CNS.

26
Antidotes Oximes

• Reverses the binding of the nerve agent to the
  enzyme, especially if given prior to aging. Also
  acts as a scavenger and inactivates circulating
  nerve agents.
• Pralidoxime Slow IV bolus. Dose is 2550 mg/kg
  in children or 2 g in adults, targeting a serum
  level of gt 4 mg/L. If given IM using the
  auto-injector, level is achieved in 8 minutes.
• May repeat dose in 1 h. Effect is lost after 3 h
  of exposure to sarin because of aging.

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Antidotes Oximes (continued)

• Side effect elevated BP and EKG abnormalities
• Other oximes (such as obidoxime and P2S) are used
  in other countries and have variable efficacy.
• There is ongoing research to develop better
  agents.

28
Antidotes Benzodiazepines

• Used to treat the seizures
• Diazepam IM/IV appears to be better than other
  benzodiazepines.
• Dose is 5 mg IV/IM. May be repeated every 515
  minutes.

29
Antidotes Pyridostygmine

• Subjects pretreated with pyridostigmine will be
  less vulnerable to nerve agents.
• The U.S Army used pyridostigmine during the Gulf
  War.
• Pyridostigmine is a carbamate that binds
  reversibly to AChE. It does not cross the CNS.
• Pretreated individuals will have a store of AChE
  that is bound to pyridostigmine and is protected
  from the nerve agent.

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Antidotes Pyridostygmine (continued)

• Bound pyridostigmine-AChE spontaneously breaks
  after several hours, releasing normal AChE.
  Administration of 2-PAM stimulates release of
  AChE that was protected from the nerve agent by
  pyridostigmine.

31
Antidotes Pyridostigmine
32
Antidotes MARK I Kit

• Contains pralidoxime (600 mg) and atropine (2 mg)
  self injectors

33
Psychological Impact

• Psychological impact has been seen after exposure
  to nerve agents as well as other terrorist
  attacks.
• Post traumatic stress disorder seen in 60 of
  victims of the Tokyo sarin gas attack at
  6 months.
• Fear of riding the subway, nightmares, and
  depression were some of the common symptoms
  (Kawana N, Ishimatsu S, Kanda K.
  Psycho-physiological effects of the terrorist
  sarin attack on the Tokyo subway system. Military
  Medicine 166(12 Suppl)236, 2001 Dec.).

34
Experimental Therapies for Nerve Agent Exposure

• Exogenous choline esterases to bind the nerve
  agents
• Paroxinases that degrade the nerve agents
• Hl-6 thought to work better than pralidoxime for
  exposure to soman, which ages quickly. HI-6 has
  been shown to work when it is administered to
  rats up to 2 hours before exposure (Kassa J,
  Fusek J. The influence of oxime selection on the
  efficacy of antidotal treatment of soman-poisoned
  rats. Acta Medica 45(1)1927, 2002).

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Helpful Resources

• http//www.bt.cdc.gov/agent
• Your regional poison center
• Medical Management of Chemical Casualties
  Handbook (http//www.fas.org/nuke/guide/usa/doctri
  ne/army/mmcch/NervAgnt.htm)

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Acknowledgments

• Edwin M. Kilbourne, MD
• Joshua Schier, MD