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Nerve agents

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Title: 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).

14
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
15
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.

16
Clinical Presentation
  • Muscarinic
  • SLUDGE BBBs
  • Salivation Bradycardia
  • Lacrimation Bronchorrhea
  • Urination Bronchospasm
  • Diaphoresis
  • GI distress (diarrhea, vomiting)
  • Emesis
  • Miosis

17
Clinical Presentation (continued)
  • Nicotinic MTWThF
  • Mydriasis
  • Tachycardia
  • Weakness
  • Hyperthermia
  • Fasciculation

18
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

19
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.

24
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.

27
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.

30
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).

35
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)

36
Acknowledgments
  • Edwin M. Kilbourne, MD
  • Joshua Schier, MD
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