Briefing Incapacitating Agents PDF

Incapacitating Agents
U.S. Army Medical Research Institute of Chemical Defense
Chemical Casualty Care Division
USAMRICD
PROTECT, PROJECT, SUSTAIN
Objectives
Definition History Representative compounds Glycolate anticholinergics: BZ and Agent 15

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History Physicochemical properties Pharmacokinetics (ADBE) Mechanism of action (pharmacodynamics) Clinical presentation of casualties Treatment
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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, debilitating , as in an incapacitating disease Showing an expected toxic effect, effect, as in ICt 50 = incapacitating Ct50 (better: ECt50 for effective Ct 50) Referring to a specific class of chemicalchemical- warfare agents, agents, as in incapacitating agents
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USAMRICD
Classification of Official CW Agents

Toxic agents (causing injury or death)
Nerve Agents GA GA, , GB GB, , GD GD, , GF GF, , VX Vesicants
H , H D , H T, T , L , H L, L , T L, L , C X , [riot control agents] [T[T - 2 m y c o t o x i n s ]
Pulmonary agents
Phosgene (CG ( CG), ), diphosgene (DP (DP), ), chlorine, [PFIB] [smokes] [vesicants]
Blood agents
Hydrogen cyanide (AC (AC), ), cyanogen chloride (CK (CK) )
Incapacitating agents (causing temporary nonlethal effects)

BZ BZ, , others
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Agents Excluded by FM 8-285

Herbicides Smoke and Flame Riot-control Agents
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Incapacitating Agents and Incapacitation

Significant incapacitation (limits combat ability)
Temporary incapacitation (hours to days)
Nonfatal incapacitation
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Types of Temporary Incapacitation

Physiological
Diarrhea Hyperthermia Mucous-membrane irritation
Mental (psychochemical, behavioral)

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Confusion Hallucinations Loss of motivation

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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

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Settings for Possible Use

Military settings
Large-scale battlefield use Special Forces
Civilian settings

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Terrorist use Prison riots Hijackings Hostage situations Recalcitrant sequestered individuals or groups
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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
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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

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Early Military Use

600 BC: Solon
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
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Alleged Modern Use

Soviet use in Afghanistan? Soviet use internally in the former Soviet Union? Brainwashing of POWs in North Korea? Other instances?
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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

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A New Twist
London, Feb 9, 1998 (Reuters): Britain on Monday released what it said was new information on chemical chemical weapons which were in Iraqs arsenal at the time of the 1991 Gulf Gulf War. . . . We have recently received intelligence indicating that . . . Iraq Ir aq may have possessed large quantities of a chemical warfare mental incapacitant agent known as Agent 15, 15, [Defence Minister George] Robertson said. . . . The Ministry of Defence described Agent 15 as one of a large group group of chemicals called glycollates which interfered with the central and peripheral nervous system.
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USAMRICD
Classification
Irritants
Riot Riot- control agents (CS, CN, etc.); pepper spray
CNS stimulants
Amphetamines, cocaine, caffeine, nicotine, strychnine, metrazole
CNS depressants
Barbiturates, opiods, antipsychotics, benzodiazepines
Psychedelics
LSD LSD-25, psilocybin, ibogaine, harmine MDMA (ecstasy), PCP
Deliriants
Many drugs, but especially anticholinergics (BZ, Agent 15)
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USAMRICD
Riot-control Agents
CS CN (commercial); Mace CA (WW I, buried) CR (British agent; U.S. Army approved) DM (vomiting agent) Pepper sprays
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Riot-control Agents: Characteristics

Aerosolized solids Low effective amount High lethal amount High safety ratio Rapid onset Short duration
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USAMRICD
Pepper Sprays: Capsaicin

Calyx Shoulder Seeds Peduncle Calyx Margin Base Capsaicin & Capsaicinoid Glands Placental Wall Placenta Exocarp (Skin) Mesocarp Endocarp Apex (Blossom End)
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USAMRICD
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
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USAMRICD
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!
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USAMRICD
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. 164-167 C Can be dispersed even by heat-producing munitions
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USAMRICD
Other Anticholinergic Glycolates

Atropine Scopolamine Oxybutynin (Ditropan) Anticholinergic antihistamines Benactyzine
One component of 1970s nerve-agent antidote TAB (TMB-4, atropine, and benactyzine)
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USAMRICD
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
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Nerve Transmission
ACh
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Nerve Transmission
ACh
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Nerve Transmission
ACh
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Impulse Termination
AChE
ACh
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Impulse Termination
AChE
ACh
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Exposure to Nerve Agent
AChE
ACh M_Incaps 30
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Exposure to Nerve Agent

AChE
ACh
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Effects on Smooth and Cardiac Muscle

AChE
ACh
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Effects on Exocrine Glands

AChE
ACh
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ACh at Receptors
Nicotinic Nicotinic ACh ACh
Muscarinic
Muscarinic
ACh
ACh
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Atropine at Receptors
Nicotinic Nicotinic Atropine Atropine
Muscarinic
Muscarinic Atropine
Atropine
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ACh and Atropine at Receptors

Nicotinic Atropine ACh Nicotinic
ACh Muscarinic Muscarinic
ACh
Atropine
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Effects of Atropine on Smooth Muscle

Nerve agent present; too much ACh in NMJ
AChE Atr Atr Atr Atr Atr Atr Atr
Atr Atr Atr Atr Atr Atr Atr Atr Atr Atr Atr Atr M_Incaps 37
ACh
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Effects of Atropine on Exocrine Glands

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

Nerve agent present; too much ACh in NMJ
AChE Atr Atr Atr Atr Atr
Atr Atr Atr ACh
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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 mAChR) ) Insufficient ACh reaching the end organ; not not enough green dots 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)
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USAMRICD
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
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normal rate or mild bradycardia
USAMRICD
Central Effects of Anticholinergics

Qualitatively similar Effective doses vary between compounds Marked confusion results from

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12-14 mg of atropine 2 mg of scopolamine 1 mg or less of BZ ? of Agent 15
USAMRICD
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
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USAMRICD
BZ: Physical Properties

Molecular formula C21H23NO3; MW 337.41 White crystalline solid; m.p. 164-167 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
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USAMRICD
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
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No detector currently available
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BZ: Physiological Data

LCt50: ICt50: 200,000 mg min / m3 112 mg min / m3
Onset of effects
0.5-4 hours after ingestion or inhalation (mean 2 hours; range 0.5-20 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)
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USAMRICD
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 dry as a bone) bone)
Cardiac effects
Heart rate labile (tachycardia x 11 -2 days not useful in diagnosis normal or bradycardia);
Gastrointestinal effects
Decreased motility and decreased secretions
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USAMRICD
BZ: Peripheral Effects II

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

Dose-dependent decrease in level of consciousness
Drowsiness sedation stupor coma
Perceptual disturbances ( (mad mad as a hatter) 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
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USAMRICD
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, clichs, and profanity Handwriting deterioration Inability to converse meaningfully
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USAMRICD
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

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

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BZ: Clinical Course

1. Onset (induction): 0 -4 hours after exposure
Parasympathetic blockade and mild CNS effects
2. Second phase: 4 -20 hours after exposure

Stupor (with ataxia and hyperthermia)
3. Third phase: 20-96 hours after exposure

Delirium (often fluctuating from moment to moment)
4. Fourth phase (resolution): following third phase

Paranoia; deep sleep
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USAMRICD
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
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DDx for Incapacitants II

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

Agent(s): State(s): Body site(s): Effects: Severity: Time course: Other diagnoses: Synergism: Type(s) and toxicity (including LD50 ) Solid? Liquid Liquid? ? Gas? Vapor Vapor? ? Aerosol? Where exposed / Route(s) of entry? [absorption] Local? Systemic? [ distribution] Mild? Moderate? Severe? Onset of symptoms? Getting better/worse? Prognosis? Instead of? [DDx] In addition to? Combined effects of multiple exposures or insults?
Remember the combination of central and peripheral effects!
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BZ: Treatment
Protect yourself! General supportive therapy
Decontamination with soap and water Observation and (in 5050- 80% of cases) restraint Management of heat stress Early evacuation
Specific antidotal therapy

Physostigmine
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USAMRICD
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
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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 45-60 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
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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 respiratoryrespiratory-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 route safer)
Drug interactions during surgery

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Promethazine may prolong neuromuscular blockade Antimuscarinics may antagonize action Barbiturates may cause addictive bronchospasm Polarizing and nondepolarizing NM blockers
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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)
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Briefing Incapacitating Agents PDF

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Incapacitating Agents

Chemical Casualty Care Division

Incapacitating Agents: Definition

Classification of Official CW Agents

Incapacitating agents (causing temporary nonlethal effects)

Agents Excluded by FM 8-285

Incapacitating Agents and Incapacitation

Temporary incapacitation (hours to days)

Types of Temporary Incapacitation

Mental (psychochemical, behavioral)

Confusion Hallucinations Loss of motivation

Potential Agents for Civilian Use

Fentanyl congeners (e.g., sufentanil)

Antipsychotic compounds (e.g., haloperidol) Anticholinergic compounds

Settings for Possible Use

Military Criteria for a Good Incapacitant

Effects reproducible and predictable

Civilian Criteria for a Good Incapicitant

Effects need not be primarily on CNS

Effects reproducible and predictable

Early Military Use

200 BC: Carthaginians

184 BC: Hannibal

AD 1500s and 1600s: Moslems

Alleged Modern Use

U.S. Interest in Incapacitants

CIA interest in psychotomimetics from early 1950s

Riot-control Agents: Characteristics

Pepper Sprays: Capsaicin

Riot Control Agents: General

Riot Control Agents: General

Wide variety of compounds BZ is a stable crystalline solid

Other Anticholinergic Glycolates

Peripheral muscarinic effects

Central muscarinic effects

Exposure to Nerve Agent

Exposure to Nerve Agent

Effects on Smooth and Cardiac Muscle

Effects on Exocrine Glands

ACh and Atropine at Receptors

ACh Muscarinic Muscarinic

Effects of Atropine on Smooth Muscle

Effects of Atropine on Exocrine Glands

Effects of Atropine on Skeletal Muscle: None!

Atr Atr Atr ACh

Peripheral Effects of Anticholinergics

Effects on Heart Rate

normal rate or mild bradycardia

Central Effects of Anticholinergics

12-14 mg of atropine 2 mg of scopolamine 1 mg or less of BZ ? of Agent 15

BZ: Physical Properties

BZ: Dispersal, Absorption, and Detection

No detector currently available

BZ: Physiological Data

BZ: Peripheral Effects I

BZ: Peripheral Effects II

BZ: Central Effects I

Perceptual disturbances ( (mad mad as a hatter) hatter )

Disturbances in judgment and insight

BZ: Central Effects II

Short-term memory loss

Deficits of expression and comprehension

BZ: Central Effects III