1. Incapacitating Agents
U.S. Army Medical Research Institute of Chemical Defense
Chemical Casualty Care Division

2. Objectives Definition History Representative compounds
Glycolate anticholinergics: BZ and Agent 15
Physicochemical properties
Pharmacokinetics (ADBE)
Mechanism of action (pharmacodynamics)
Clinical presentation of casualties
Treatment

3. Incapacitating Agents: Definition
CW agents designed not to injure or kill but to induce disorientation or other temporary effects leading to impaired performance
“Incapacitating” unfortunately an ambiguous term
Rendering powerless; debilitating, as in “an incapacitating disease”
Showing an expected toxic effect, as in “ICt50 = incapacitating Ct50” (better: ECt50 for “effective Ct50”)
Referring to a specific class of chemical-warfare agents, as in “incapacitating agents”

4. Classification of “Official” CW Agents
Toxic agents (causing injury or death)
Nerve Agents
GA, GB, GD, GF, VX
Vesicants
H, HD, HT, L, HL, TL, CX, [riot control agents] [T-2 mycotoxins]
Pulmonary agents
Phosgene (CG), diphosgene (DP), chlorine, [PFIB] [smokes] [vesicants]
“Blood” agents
Hydrogen cyanide (AC), cyanogen chloride (CK)
Incapacitating agents (causing temporary nonlethal effects)
BZ, others

5. Agents Excluded by FM 8-285 Herbicides Smoke and Flame
Riot-control Agents

6. Incapacitating Agents and “Incapacitation”
Significant incapacitation (limits combat ability)
Temporary incapacitation (hours to days)
Nonfatal incapacitation

7. Types of Temporary Incapacitation
Physiological
Diarrhea
Hyperthermia
Mucous-membrane irritation
Mental (“psychochemical,” behavioral)
Confusion
Hallucinations
Loss of motivation

8. Potential Agents for Civilian Use
Riot-control agents
Rapidly acting volatile anesthetic agents
Rapidly acting barbiturates
Methohexital
Fentanyl congeners (e.g., sufentanil)
Effects reversed by naloxone
Antipsychotic compounds (e.g., haloperidol)
Anticholinergic compounds

9. Settings for Possible Use
Military settings
Large-scale battlefield use
Special Forces
Civilian settings
Terrorist use
Prison riots
Hijackings
Hostage situations
Recalcitrant sequestered individuals or groups

10. Military Criteria for a Good Incapacitant
High potency
High safety ratio
Logistically feasible (easily disseminated)
Duration of hours to days (to disrupt combat ability)
Effects: Impairment of higher CNS functions
Confusion, disorientation, and behavioral disruption
Effects reproducible and predictable

11. Civilian Criteria for a Good Incapicitant
Very high safety ratio
Very short onset time (seconds to minutes)
Very short duration of effects (10 to 60 minutes)
Amenable to treatment with specific antidote
Feasible for small-scale use against mixed groups
Criminals with hostages
Effects need not be primarily on CNS
Immobilization, diarrhea, loss of coordination, blindness, loss of consciousness, disorientation
Effects reproducible and predictable

12. Early Military Use 600 BC: Solon 200 BC: Carthaginians
Hellebore roots thrown into river diarrhea
200 BC: Carthaginians
Mandragora-laced wine narcosis
184 BC: Hannibal
Snake-filled pots thrown onto decks panic, confusion
Belladonna alkaloids disorientation
AD 1500s and 1600s: Moslems
Hashish used on own troops to foster fearlessness

13. Alleged Modern Use Soviet use in Afghanistan?
Soviet use internally in the former Soviet Union?
Brainwashing of POWs in North Korea?
Other instances?

14. U.S. Interest in Incapacitants
Military interest in possibilities of LSD-25
Military research and development
Antipsychotic “tranquilizers”
Cannabinoids (marijuana congeners)
Indoles (LSD and congeners)
Anticholinergic compounds
BZ manufactured and stockpiled
CIA interest in psychotomimetics from early 1950s

15. A New Twist
London, Feb 9, 1998 (Reuters): Britain on Monday released what it said was new information on chemical weapons which were in Iraq’s arsenal at the time of the 1991 Gulf War “We have recently received intelligence indicating that Iraq may have possessed large quantities of a chemical warfare mental incapacitant agent known as Agent 15,” [Defence Minister George] Robertson said The Ministry of Defence described Agent 15 as one of a large group of chemicals called glycollates which interfered with the central and peripheral nervous system.

16. Classification Irritants CNS stimulants CNS depressants Psychedelics
Riot-control agents (CS, CN, etc.); pepper spray
CNS stimulants
Amphetamines, cocaine, caffeine, nicotine, strychnine, metrazole
CNS depressants
Barbiturates, opiods, antipsychotics, benzodiazepines
Psychedelics
LSD-25, psilocybin, ibogaine, harmine
MDMA (“ecstasy”), PCP
Deliriants
Many drugs, but especially anticholinergics (BZ, Agent 15)

17. Riot-control Agents CS CN (commercial); Mace ® CA (WW I, buried)
CR (British agent; U.S. Army approved)
DM (vomiting agent)
Pepper sprays

18. Riot-control Agents: Characteristics
Aerosolized solids
Low effective amount
High lethal amount
High safety ratio
Rapid onset
Short duration

19. Pepper Sprays: Capsaicin
Peduncle
Calyx Margin
Base
Capsaicin & Capsaicinoid Glands
Placental Wall
Placenta
Exocarp (Skin)
Mesocarp
Endocarp
Apex (Blossom End)
Seeds
Shoulder
Calyx

20. Riot Control Agents: General
Used for riot control in 1912 in France and became the first noxious chemicals used in World War I (Aug 1914); CS and CN (Mace®) still widely used
Not recognized by the U.S. as official chemical agents
Very persistent agents usually dispersed as solids or in solution; low volatility, so no appreciable vapor hazard

21. Riot Control Agents: General
Lacrimators (CA, CN, CS, CR) and a vomiting agent (DM) with short onset, short duration, and high safety ratios
Usually self-limited effects (irritation, pain, lacrimation, coughing, etc.) on eyes, respiratory mucosa, and skin (plus vomiting with DM); long-term sequelae uncommon
When decontamination is required, avoid bleach!

22. Anticholinergics: General
All are glycolates (esters of glycolic acid, HOCH2COOH)
Contain -COH-CO-O- moiety
Usually contain aromatic moieties
Wide variety of compounds
BZ is a stable crystalline solid
m.p C
Can be dispersed even by heat-producing munitions

23. Other Anticholinergic Glycolates
Atropine
Scopolamine
Oxybutynin (Ditropan)
Anticholinergic antihistamines
Benactyzine
One component of 1970s nerve-agent antidote TAB (TMB-4, atropine, and benactyzine)

24. Anticholinergics: Actions
Block acetylcholine (ACh)
Opposite effects from nerve agents
Peripheral muscarinic effects
At muscarinic receptors (mAChR) in
Smooth muscle
Exocrine glands
Central muscarinic effects
On muscarinic ACh receptors (mAChR) in the CNS

25. Nerve Transmission
ACh

26. Nerve Transmission
ACh

27. Nerve Transmission
ACh

28. Impulse Termination
AChE
ACh

29. Impulse Termination
AChE
ACh

30. Exposure to Nerve Agent
ACh
AChE

31. Exposure to Nerve Agent
ACh
AChE

32. Effects on Smooth and Cardiac Muscle
AChE
ACh

33. Effects on Exocrine Glands
AChE
ACh

34. ACh at Receptors
ACh
Nicotinic
Nicotinic
Muscarinic
Muscarinic

35. Atropine at Receptors
Nicotinic
Muscarinic
Atropine

36. ACh and Atropine at Receptors
Nicotinic
Muscarinic
Atropine

37. Effects of Atropine on Smooth Muscle
Nerve agent present;
too much ACh in NMJ
Atr
Atr
Atr
Atr
Atr
AChE
Atr
Atr
Atr
Atr
Atr
Atr
Atr
Atr
Atr
Atr
Atr
ACh
Atr
Atr
Atr

38. Effects of Atropine on Exocrine Glands
Nerve agent present;
too much ACh in NGJ
Atr
ACh
AChE

39. Effects of Atropine on Skeletal Muscle: None!
Nerve agent present;
too much ACh in NMJ
Atr
Atr
AChE
Atr
Atr
Atr
Atr
Atr
Atr
ACh

40. Peripheral Effects of Anticholinergics
When ACh is not present in excess in the synapse, the NMJ, or the NGJ, anticholinergics still decrease the effective concentration of ACh at the muscarinic receptor (mAChR)
Insufficient ACh reaching the end organ; “not enough green dots”
Under these circumstances, the peripheral effects at muscarinic sites are those of understimulation of end organs (smooth muscle and exocrine glands)
No direct effects at nicotinic sites (skeletal muscle)

41. Effects on Heart Rate Qualitatively different between compounds
Atropine
Initial brief tachycardia pronounced tachycardia
Scopolamine
Moderate tachycardia prolonged tachycardia BZ
Tachycardia x 1-2 days normal rate or mild bradycardia

42. Central Effects of Anticholinergics
Qualitatively similar
Effective doses vary between compounds
Marked confusion results from
12-14 mg of atropine
2 mg of scopolamine
1 mg or less of BZ
? of Agent 15

43. BZ (QNB) 3-Quinuclidinyl benzilate (QNB); Oksilidin
Developed by a pharmaceutical company during a search for a new GI drug
Called BZ because of benzilate and also because of its “buzz” (~3 Mark I injections without nerve agent)
The only incapacitating agent weaponized by the U.S.
Demilitarization of BZ stockpiles began in 1988

44. BZ: Physical Properties
Molecular formula C21H23NO3; MW
White crystalline solid; m.p C; b.p. 320 C
Odorless; negligible vapor pressure and volatility
Stable in most materials
Half-life is 3-4 weeks in moist air
Very persistent in soil and water and on most surfaces

45. BZ: Dispersal, Absorption, and Detection
Dispersal usually as a solid suspended in air (“aerosol”)
Routes of entry (absorption)
Inhalation (primary route)
Ingestion (effective secondary route)
Percutaneous absorption (especially with DMSO or other appropriate solvents)
Detection
No detector currently available

46. BZ: Physiological Data
LCt50: ,000 mg • min / m3
ICt50: mg • min / m3
Onset of effects
0.5-4 hours after ingestion or inhalation (mean 2 hours; range hours)
Effects may not appear until 36 hours after skin exposure
Duration of effects
72-96 hours; dose-dependent (from an ICt50, severe effects last 36 hours; mild effects persist for 45 hours)

47. BZ: Peripheral Effects I
Ocular effects
Mydriasis (dilated pupils) lasting several days
Paralysis of accommodation impairment of near vision
Oral effects
Xerostomia (dry mouth); drying of secretions; thirst (“dry as a bone”)
Cardiac effects
Heart rate labile (tachycardia x 1-2 days normal or bradycardia); not useful in diagnosis
Gastrointestinal effects
Decreased motility and decreased secretions

48. BZ: Peripheral Effects II
Cutaneous effects
Decreased sweating (“dry as a bone”)
“Atropine flush” (“red as a beet”)
Heat retention hyperthermia (“hot as a hare”)
Genitourinary effects
Decreased bladder tone and decreased urinary force (“dry as . . .”)
Severe bladder distention
Neuromuscular effects
Incoordination, heightened stretch reflexes, ataxia, and muscle weakness (why?)

49. BZ: Central Effects I
Dose-dependent decrease in level of consciousness
Drowsiness sedation stupor coma
Perceptual disturbances (“mad as a hatter”)
Illusions
Visual hallucinations (realistic, distinct, panoramic, and decreasing in size over time)
Disturbances in judgment and insight
Lack of social restraint profanity and vulgarity
Inability to use perceptual cues
Denial and confabulation

50. BZ: Central Effects II Attention and memory deficits
Easy distractibility
Short-term memory loss
Deficits of expression and comprehension
Slurred, often senseless speech
Flat, uninflected tone of voice
Perseveration
Concrete, semiautomatic speech with colloquialisms, clichés, and profanity
Handwriting deterioration
Inability to converse meaningfully

51. BZ: Central Effects III
Disorientation to time and place
Disrobing, mumbling, and picking (“woolgathering”)
Ataxia
Behavioral lability
Swings between quiet confusion and combativeness
Paranoia as other symptoms are resolving

52. Psychosocial Aspects Sharing of illusions and hallucinations
Folie à deux
Folie en famille
“Mass hysteria”
Similarity to psychogenic conditions
May prove hazardous

53. BZ: Clinical Course 1. Onset (induction): 0-4 hours after exposure
Parasympathetic blockade and mild CNS effects
2. Second phase: hours after exposure
Stupor (with ataxia and hyperthermia)
3. Third phase: hours after exposure
Delirium (often fluctuating from moment to moment)
4. Fourth phase (resolution): following third phase
Paranoia; deep sleep

54. DDx for Incapacitants I
Anticholinergic compounds, indoles, cannabinoids, anxiety reactions, other intoxications (alcohol, bromides, lead, barbiturates)
Restlessness, lightheadedness, vertigo, failure to obey orders, confusion, erratic behavior, stumbling or staggering, vomiting
Anticholinergics
Dryness of mouth and skin, flushing, hyperthermia, mydriasis, slurred speech, hallucinations (vivid, realistic, decreasing in size), disrobing, “phantom behaviors” (plucking or picking clothes or air), mumbling, stupor, labile sensorium

55. DDx for Incapacitants II
Indoles (LSD); schizophrenic psychosis
Inappropriate smiling or laughing, irrational fear, distractibility, difficulty expressing self, perceptual distortions, stomach cramps, vomiting, labile changes in HR / BP / mydriasis
Cannabinoids (THC)
Euphoria, relaxation, day-dreaming, unconcerned attitude, easy laughter, orthostatic hypotension
Anxiety reaction
Tremor, clinging or pleading, crying, alertness, orientation, history of nervousness or immaturity, phobias, paralysis, blindness

56. Incapacitants and ASBESTOS
Agent(s): Type(s) and toxicity (including LD50)
State(s): Solid? Liquid? Gas? Vapor? Aerosol?
Body site(s): Where exposed / Route(s) of entry? [absorption]
Effects: Local? Systemic? [distribution]
Severity: Mild? Moderate? Severe?
Time course: Onset of symptoms? Getting better/worse? Prognosis?
Other diagnoses: Instead of? [DDx] In addition to?
Synergism: Combined effects of multiple exposures or insults?
Remember the combination of central and peripheral effects!

57. BZ: Treatment Protect yourself! General supportive therapy
Decontamination with soap and water
Observation and (in 50-80% of cases) restraint
Management of heat stress
Early evacuation
Specific antidotal therapy
Physostigmine

58. Physostigmine
A carbamate anticholinesterase derived from elixir of calabar bean (African ordeal poison)
Nonpolar compound, so crosses blood-brain barrier and thus can act centrally as well as peripherally
Eserine (physostigmine) and Antilirium (physostigmine salicylate)
Antilirium erroneously called a “universal antidote”
Specific action is to elevate ACh by inhibiting AChE
Used to treat poisoning from cholinergic agents and TCAs

59. Physostigmine: Pearls of Therapy
Minimally effective during first 4 hours after exposure
Very effective after 4 hours when administered IM or PO
Oral dosing requires 1.5 times the dose given IM
Effects last only about minutes
Redose frequently or start slow IV infusion
Physostigmine does NOT shorten the clinical course of anticholinergic poisoning; relapses will occur if treatment is discontinued prematurely

60. Physostigmine: Cautions
Side effects: Cholinergic (nerve-agent-like)
Usually requires only dosage reduction
Moderate overdose: Dyspnea and decreased vital capacity
Large overdose: Apnea secondary to respiratory-muscle fatigue
Complications
Convulsions and severe cardiac dysrhythmias from IV administration if rate is too rapid or if patient is acidotic or hypoxic (IM route safer)
Drug interactions during surgery
Promethazine may prolong neuromuscular blockade
Antimuscarinics may antagonize action
Barbiturates may cause addictive bronchospasm
Polarizing and nondepolarizing NM blockers

61. Incapacitating Agents: Summary
Designed to create temporary nonlethal performance impairment (“incapacitation”)
Main drawback to military or civilian use: Unpredictability
Only known weaponized agents: BZ (QNB) and Agent 15
BZ is a delayed-onset anticholinergic glycolate with both central and peripheral muscarinic effects
Delayed onset, labile presentation, and prolonged course
Specific antidote: Physostigmine (a carbamate anticholinesterase that crosses the blood-brain barrier)