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Outline

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

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

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”

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

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

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

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

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

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

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

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

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

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

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

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.

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)

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

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

Pepper Sprays: Capsaicin

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

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!

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

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

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

Nerve Transmission

Nerve Transmission

Nerve Transmission

Impulse Termination

Impulse Termination

Exposure to Nerve Agent

Exposure to Nerve Agent

Effects on Smooth and Cardiac Muscle

Effects on Exocrine Glands

ACh at Receptors

Atropine at Receptors

ACh and Atropine at Receptors

Effects of Atropine on Smooth Muscle

Effects of Atropine on Exocrine Glands

Effects of Atropine on Skeletal Muscle: None!

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)

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

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

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

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

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

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)

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

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?)

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

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

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

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

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

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

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

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!

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

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

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

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

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)