Fourth Generation Agents





These guidelines were developed as part of ongoing preparedness for all hazards and are intended to support fire, EMS, and hospital staff in the medical management of patients if an incident occurs involving a fourth generation agent (FGA, also known as A-series or Novichok nerve agents), such as the one used in the United Kingdom (U.K.) in 2018. No illicit use or manufacture of an FGA or other nerve agent is known to have occurred in the United States (U.S.), and there is no known threat of any nerve agent use in the U.S.

The guidance is intended for fire and EMS first responders and hospital staff. As part of ongoing standard preparedness, jurisdictions should update their existing plans with this information and integrate it into in-service training curricula.

Limited experiential and research data specific to FGAs are available. These guidelines will be updated as additional insights are gained.

If you suspect a nerve agent poisoning incident, ensure emergency services are aware through 911 and the local FBI Weapons of Mass Destruction (WMD) Coordinator is notified immediately. Contact your regional poison center (1-800-222-1222) for additional patient management information.

If FGA presence is suspected or confirmed, the U.S. government can assemble a group of subject matter experts to provide medical advice to local authorities and providers upon request.


Nerve agents are extremely toxic chemical warfare agents. They are generally categorized as either volatile or low volatility chemicals. A volatile chemical evaporates readily, forming a vapor; exposure would most likely occur from breathing in chemical vapor and symptoms would appear soon (often within seconds to minutes) after inhalation. Most exposures to low volatility agents are from dermal contact. Signs and symptoms may be delayed for hours to even days (latent period). However, under certain circumstances, low volatility agents may be inhaled, in which case symptoms would rapidly ensue. Sarin is an example of a volatile nerve agent, whereas VX is a low volatility agent. Ingestion, eye exposure, and contact with mucous membranes are additional possible routes of exposure for both volatile and low volatility nerve agents.

Fourth generation agents are low volatility nerve agents that evaporate even less readily than VX. FGAs are at least as potent as VX; it takes a lower, or a similar, dose of an FGA compared to VX to cause adverse health effects or death. All nerve agents inhibit acetylcholinesterase (AChE), an enzyme that normally breaks down the neurotransmitter acetylcholine (ACh). The inhibition of AChE results in an excess of ACh at muscarinic and nicotinic receptors in the brain, in skeletal and smooth muscle, and in exocrine glands (e.g., tear, salivary, bronchial, and sweat glands). This results in hyperactivity in these target organs, a condition called cholinergic crisis. Organophosphorus and carbamate pesticides also inhibit AChE and produce similar effects to nerve agents.

Medical providers need to keep in mind that those variables (e.g., the specific agent and dose, including concentration and duration of exposure; physical states of the agent in the environment; routes of exposure; time from exposure to treatment; and underlying medical conditions) determine toxicity, clinical manifestations, and effectiveness of medical interventions. Therefore, a spectrum of clinical effects among the nerve agents and among individual patients is expected.

What You Should Know About all Nerve Agents

  • Nerve agents are extremely toxic and can cause rapid loss of consciousness, convulsions, and death from respiratory failure.
  • Nerve agents are readily absorbed by inhalation, ingestion, and dermal contact. Rapidly fatal systemic effects may occur.
  • The time course of health effects depends on the agent, route of exposure, and other factors, with inhalation causing the most rapid effects and dermal contact associated with a longer (hours to days) latent period.
  • Patients whose skin, clothing, or personal effects are contaminated with nerve agent can expose rescuers by direct contact or through evaporation of vapor (“off-gassing”). Patients whose skin is exposed only to nerve agent vapor pose minimal risk of secondary exposure; however, clothing can trap vapor.
  • Along with supportive care and patient decontamination, anticholinergics (e.g., atropine), oxime AChE reactivators (e.g., pralidoxime chloride (2-PAM)), and anticonvulsants (e.g., the benzodiazepines - diazepam, midazolam, and lorazepam) are the mainstays of the management of nerve agent toxicity.

Managing Nerve Agent Exposure

ABCDDs: Airway, Breathing, Circulation (supportive care), Decontamination, and Drugs (anticholinergics, reactivators, and anticonvulsants)

Additional Considerations

Find more information on this substance at: PubChem, PubMed