Transcript INITIAL TRIAGE AND MEDICAL MANAGEMENT OF CHEMICAL …

Incapacitating Agents
Incapacitating Agents
U.S. Army Medical Research Institute of Chemical Defense
Chemical Casualty Care Division
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Incapacitating Agents
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, 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”
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Incapacitating Agents
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
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Incapacitating Agents
Agents Excluded by FM 8-285
• Herbicides
• Smoke and Flame
• Riot-control Agents
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Incapacitating Agents
Incapacitating Agents and “Incapacitation”
• Significant incapacitation (limits combat ability)
• Temporary incapacitation (hours to days)
• Nonfatal incapacitation
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Incapacitating Agents
Types of Temporary Incapacitation
• Physiological
• Diarrhea
• Hyperthermia
• Mucous-membrane irritation
• Mental (“psychochemical,” behavioral)
• Confusion
• Hallucinations
• Loss of motivation
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Incapacitating Agents
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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Incapacitating Agents
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
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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
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.
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Incapacitating Agents
Classification
• Irritants
• 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)
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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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Incapacitating Agents
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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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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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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Incapacitating Agents
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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Incapacitating Agents
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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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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Incapacitating Agents
Nerve Transmission
ACh
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Incapacitating Agents
Nerve Transmission
ACh
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Incapacitating Agents
Nerve Transmission
ACh
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Incapacitating Agents
Impulse Termination
AChE
ACh
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Incapacitating Agents
Impulse Termination
AChE
ACh
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Incapacitating Agents
Exposure to Nerve Agent
AChE
ACh
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Incapacitating Agents
Exposure to Nerve Agent
AChE
ACh
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Incapacitating Agents
Effects on Smooth and Cardiac Muscle
AChE
ACh
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Effects on Exocrine Glands
AChE
ACh
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Incapacitating Agents
ACh at Receptors
Nicotinic
Nicotinic
ACh
ACh
Muscarinic
ACh
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Muscarinic
ACh
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Atropine at Receptors
Nicotinic
Atropine
Nicotinic
Atropine
Muscarinic
Atropine
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Muscarinic
Atropine
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ACh and Atropine at Receptors
Nicotinic
Nicotinic
Atropine
ACh
ACh
Muscarinic
ACh
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Muscarinic
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
ACh
Atr
Atr
Atr
Atr
Atr
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Effects of Atropine on Exocrine Glands
Nerve agent present;
too much ACh in NGJ
Atr
Atr
Atr
AChE
Atr
Atr
Atr
Atr
Atr
Atr
Atr
Atr
ACh
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Atr
Atr
Atr
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Effects of Atropine on Skeletal Muscle: None!
Nerve agent present;
too much ACh in NMJ
Atr
AChE
Atr
Atr
Atr
Atr
Atr
Atr
Atr
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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)
• 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)
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Effects on Heart Rate
• Qualitatively different between compounds
• Atropine
• Initial brief tachycardia
pronounced tachycardia
• Scopolamine
• Moderate tachycardia
prolonged tachycardia
• Tachycardia x 1-2 days
normal rate or mild bradycardia
• BZ
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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
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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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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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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
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BZ: Physiological Data
• LCt50:
200,000 mg • min / m3
• ICt50:
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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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
not useful in diagnosis
normal or bradycardia);
• Gastrointestinal effects
• Decreased motility and decreased secretions
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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?)
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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
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BZ: Central Effects II
• Attention and memory deficits
• Easy distractibility
• Short-term memory loss
• Deficits of expression and comprehension
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Slurred, often senseless speech
Flat, uninflected tone of voice
Perseveration
Concrete, semiautomatic speech with colloquialisms, clichés,
and profanity
• Handwriting deterioration
• Inability to converse meaningfully
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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 à 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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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,
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
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Incapacitants and ASBESTOS
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Agent(s):
State(s):
Body site(s):
Effects:
Severity:
Time course:
Other diagnoses:
Synergism:
Type(s) and toxicity (including LD50)
Solid? Liquid? Gas? 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
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Decontamination with soap and water
Observation and (in 50-80% of cases) restraint
Management of heat stress
Early evacuation
• Specific antidotal therapy
• Physostigmine
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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 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
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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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