# Presentation: 120352

## Nerve agents  

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

## 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

## 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.

## 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.

## 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**.**

## Background (continued)

- Iraq reportedly used tabun and maybe sarin in the Iran-Iraq war (1984–1988).
- Iranian soldiers had atropine auto-injectors.
- Many had atropine overdoses from misuse of their auto-injectors.

## 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.

## 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.

## Military Designations

- Tabun= GA
- Sarin= GB
- Soman= GD
- Cyclosarin= GF
- VX

## 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.

## Toxicity

- Dermal toxicity: One drop of VX,1–10 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.

## 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.

## 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).

##          Autonomic Nervous System	      Somatic    Central

- N

**         ****Autonomic Nervous System****	****      Somatic    Central**

-          Parasympathetic	      Sympathetic

- N

- N

- N

- ACh

- ACh

- ACh

- ACh

- ACh

- M

- M

- ACh

- ACh

- A

- A

- Epinephrine

- Norepinephrine

- N

- ACh

**Sweat Glands**

**Glands**
**Bladder**
**Gut**
**Heart**

**Heart**
**Blood Pressure**

- Neuromuscular Junction

- Brain

- AutonomicGanglia

- End Organ

- M

## 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.

## Clinical Presentation

- Muscarinic:
- 	SLUDGE—				BBBs—
** ****Salivation****	****	****	****	****    Bradycardia**
** ****Lacrimation****	****	****	****  ****	****    Bronchorrhea**
** ****Urination****	****	****	****	****    Bronchospasm**
** ****Diaphoresis**
** ****GI distress (diarrhea, vomiting)**
** ****Emesis**
**	****	****	****	****	*****Miosis***

## Clinical Presentation (continued)

**Nicotinic: MTWThF **
**Mydriasis**
**Tachycardia**
**Weakness**
**Hyperthermia**
**Fasciculation**

## 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

## 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.

## 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.

## Differential Diagnosis for Nerve Agent Poisoning

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

## 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.

## 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.

## 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

## Antidotes:  Atropine

- Muscarinic receptor antagonist.
- Only treats muscarinic symptoms.
- Given IV, IM, or by ET tube.
- Dose is 2 mg every 5–10 minutes. End point is resolution of bronchorrhea.
- For children, give 0.5–1.0 mg IM/IV every 5–20 minutes. For children < 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.

## 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 25–50 mg/kg in children or 2 g in adults, targeting a serum level of > 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.

## 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.

## 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 5–15 minutes.

## 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.

## 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.

## Antidotes: Pyridostigmine

## Antidotes: MARK I Kit

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

## 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):23–6, 2001 Dec.).

## 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):19–27, 2002).

## Helpful Resources

- _[http://www.bt.cdc.gov/agent](http://www.bt.cdc.gov/agent)_
- Your regional poison center
- Medical Management of Chemical Casualties Handbook (_[http://www.fas.org/nuke/guide/usa/doctrine/army/mmcch/NervAgnt.htm](http://www.fas.org/nuke/guide/usa/doctrine/army/mmcch/NervAgnt.htm)_)

## Acknowledgments

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