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Incapacitating Agents USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents U.S. Army Medical Research Institute of Chemical Defense Chemical Casualty.

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Presentation on theme: "Incapacitating Agents USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents U.S. Army Medical Research Institute of Chemical Defense Chemical Casualty."— Presentation transcript:

1 Incapacitating Agents USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents U.S. Army Medical Research Institute of Chemical Defense Chemical Casualty Care Division

2 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 2 Objectives DefinitionDefinition HistoryHistory Representative compoundsRepresentative compounds Glycolate anticholinergics: BZ and Agent 15Glycolate anticholinergics: BZ and Agent 15 HistoryHistory Physicochemical propertiesPhysicochemical properties Pharmacokinetics (ADBE)Pharmacokinetics (ADBE) Mechanism of action (pharmacodynamics)Mechanism of action (pharmacodynamics) Clinical presentation of casualtiesClinical presentation of casualties TreatmentTreatment

3 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 3 Incapacitating Agents: Definition CW agents designed not to injure or kill but to induce disorientation or other temporary effects leading to impaired performanceCW agents designed not to injure or kill but to induce disorientation or other temporary effects leading to impaired performance “Incapacitating” unfortunately an ambiguous term“Incapacitating” unfortunately an ambiguous term Rendering powerless; debilitating, as in “an incapacitating disease”Rendering powerless; debilitating, as in “an incapacitating disease” Showing an expected toxic effect, as in “ICt 50 = incapacitating Ct 50 ” (better: ECt 50 for “effective Ct 50 ”)Showing an expected toxic effect, as in “ICt 50 = incapacitating Ct 50 ” (better: ECt 50 for “effective Ct 50 ”) Referring to a specific class of chemical-warfare agents, as in “incapacitating agents”Referring to a specific class of chemical-warfare agents, as in “incapacitating agents”

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

5 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 5 Agents Excluded by FM HerbicidesHerbicides Smoke and FlameSmoke and Flame Riot-control AgentsRiot-control Agents

6 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 6 Incapacitating Agents and “Incapacitation” Significant incapacitation (limits combat ability)Significant incapacitation (limits combat ability) Temporary incapacitation (hours to days)Temporary incapacitation (hours to days) Nonfatal incapacitationNonfatal incapacitation

7 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 7 Types of Temporary Incapacitation PhysiologicalPhysiological DiarrheaDiarrhea HyperthermiaHyperthermia Mucous-membrane irritationMucous-membrane irritation Mental (“psychochemical,” behavioral)Mental (“psychochemical,” behavioral) ConfusionConfusion HallucinationsHallucinations Loss of motivationLoss of motivation

8 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 8 Potential Agents for Civilian Use Riot-control agentsRiot-control agents Rapidly acting volatile anesthetic agentsRapidly acting volatile anesthetic agents Rapidly acting barbituratesRapidly acting barbiturates MethohexitalMethohexital Fentanyl congeners (e.g., sufentanil)Fentanyl congeners (e.g., sufentanil) Effects reversed by naloxoneEffects reversed by naloxone Antipsychotic compounds (e.g., haloperidol)Antipsychotic compounds (e.g., haloperidol) Anticholinergic compoundsAnticholinergic compounds

9 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 9 Settings for Possible Use Military settingsMilitary settings Large-scale battlefield useLarge-scale battlefield use Special ForcesSpecial Forces Civilian settingsCivilian settings Terrorist useTerrorist use Prison riotsPrison riots HijackingsHijackings Hostage situationsHostage situations Recalcitrant sequestered individuals or groupsRecalcitrant sequestered individuals or groups

10 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 10 Military Criteria for a Good Incapacitant High potencyHigh potency High safety ratioHigh safety ratio Logistically feasible (easily disseminated)Logistically feasible (easily disseminated) Duration of hours to days (to disrupt combat ability)Duration of hours to days (to disrupt combat ability) Effects: Impairment of higher CNS functionsEffects: Impairment of higher CNS functions Confusion, disorientation, and behavioral disruptionConfusion, disorientation, and behavioral disruption Effects reproducible and predictableEffects reproducible and predictable

11 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 11 Civilian Criteria for a Good Incapicitant Very high safety ratioVery high safety ratio Very short onset time (seconds to minutes)Very short onset time (seconds to minutes) Very short duration of effects (10 to 60 minutes)Very short duration of effects (10 to 60 minutes) Amenable to treatment with specific antidoteAmenable to treatment with specific antidote Feasible for small-scale use against mixed groupsFeasible for small-scale use against mixed groups Criminals with hostagesCriminals with hostages Effects need not be primarily on CNSEffects need not be primarily on CNS Immobilization, diarrhea, loss of coordination, blindness, loss of consciousness, disorientationImmobilization, diarrhea, loss of coordination, blindness, loss of consciousness, disorientation Effects reproducible and predictableEffects reproducible and predictable

12 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 12 Early Military Use 600 BC: Solon600 BC: Solon Hellebore roots thrown into river diarrheaHellebore roots thrown into river diarrhea 200 BC: Carthaginians200 BC: Carthaginians Mandragora-laced wine narcosisMandragora-laced wine narcosis 184 BC: Hannibal184 BC: Hannibal Snake-filled pots thrown onto decks panic, confusionSnake-filled pots thrown onto decks panic, confusion Belladonna alkaloids disorientationBelladonna alkaloids disorientation AD 1500s and 1600s: MoslemsAD 1500s and 1600s: Moslems Hashish used on own troops to foster fearlessnessHashish used on own troops to foster fearlessness

13 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 13 Alleged Modern Use Soviet use in Afghanistan?Soviet use in Afghanistan? Soviet use internally in the former Soviet Union?Soviet use internally in the former Soviet Union? Brainwashing of POWs in North Korea?Brainwashing of POWs in North Korea? Other instances?Other instances?

14 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 14 U.S. Interest in Incapacitants Military interest in possibilities of LSD-25Military interest in possibilities of LSD-25 Military research and developmentMilitary research and development Antipsychotic “tranquilizers”Antipsychotic “tranquilizers” Cannabinoids (marijuana congeners)Cannabinoids (marijuana congeners) Indoles (LSD and congeners)Indoles (LSD and congeners) Anticholinergic compoundsAnticholinergic compounds BZ manufactured and stockpiledBZ manufactured and stockpiled CIA interest in psychotomimetics from early 1950sCIA interest in psychotomimetics from early 1950s

15 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 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.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 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 16 Classification IrritantsIrritants Riot-control agents (CS, CN, etc.); pepper sprayRiot-control agents (CS, CN, etc.); pepper spray CNS stimulantsCNS stimulants Amphetamines, cocaine, caffeine, nicotine, strychnine, metrazoleAmphetamines, cocaine, caffeine, nicotine, strychnine, metrazole CNS depressantsCNS depressants Barbiturates, opiods, antipsychotics, benzodiazepinesBarbiturates, opiods, antipsychotics, benzodiazepines PsychedelicsPsychedelics LSD-25, psilocybin, ibogaine, harmineLSD-25, psilocybin, ibogaine, harmine MDMA (“ecstasy”), PCPMDMA (“ecstasy”), PCP DeliriantsDeliriants Many drugs, but especially anticholinergics (BZ, Agent 15)Many drugs, but especially anticholinergics (BZ, Agent 15)

17 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 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 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 18 Riot-control Agents: Characteristics Aerosolized solidsAerosolized solids Low effective amountLow effective amount High lethal amountHigh lethal amount High safety ratioHigh safety ratio Rapid onsetRapid onset Short durationShort duration

19 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 19 Pepper Sprays: Capsaicin

20 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 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 usedUsed 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 agentsNot 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 hazardVery persistent agents usually dispersed as solids or in solution; low volatility, so no appreciable vapor hazard

21 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 21 Riot Control Agents: General Lacrimators (CA, CN, CS, CR) and a vomiting agent (DM) with short onset, short duration, and high safety ratiosLacrimators (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 uncommonUsually 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!When decontamination is required, avoid bleach!

22 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 22 Anticholinergics: General All are glycolates (esters of glycolic acid, HOCH 2 COOH)All are glycolates (esters of glycolic acid, HOCH 2 COOH) Contain -COH-CO-O- moietyContain -COH-CO-O- moiety Usually contain aromatic moietiesUsually contain aromatic moieties Wide variety of compoundsWide variety of compounds BZ is a stable crystalline solidBZ is a stable crystalline solid m.p Cm.p C Can be dispersed even by heat-producing munitionsCan be dispersed even by heat-producing munitions

23 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 23 Other Anticholinergic Glycolates AtropineAtropine ScopolamineScopolamine Oxybutynin (Ditropan)Oxybutynin (Ditropan) Anticholinergic antihistaminesAnticholinergic antihistamines BenactyzineBenactyzine One component of 1970s nerve-agent antidote TAB (TMB-4, atropine, and benactyzine)One component of 1970s nerve-agent antidote TAB (TMB-4, atropine, and benactyzine)

24 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 24 Anticholinergics: Actions Block acetylcholine (ACh)Block acetylcholine (ACh) Opposite effects from nerve agentsOpposite effects from nerve agents Peripheral muscarinic effectsPeripheral muscarinic effects At muscarinic receptors (mAChR) inAt muscarinic receptors (mAChR) in Smooth muscleSmooth muscle Exocrine glandsExocrine glands Central muscarinic effectsCentral muscarinic effects On muscarinic ACh receptors (mAChR) in the CNSOn muscarinic ACh receptors (mAChR) in the CNS

25 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 25 Nerve Transmission ACh

26 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 26 Nerve Transmission ACh

27 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 27 Nerve Transmission ACh

28 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 28 Impulse Termination ACh AChE

29 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 29 Impulse Termination ACh AChE

30 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 30 Exposure to Nerve Agent ACh AChE

31 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 31 Exposure to Nerve Agent ACh AChE

32 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 32 Effects on Smooth and Cardiac Muscle ACh AChE

33 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 33 Effects on Exocrine Glands ACh AChE

34 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 34 ACh at Receptors ACh Nicotinic Muscarinic

35 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 35 Atropine at Receptors Nicotinic Muscarinic Atropine

36 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 36 ACh and Atropine at Receptors ACh Nicotinic Muscarinic Atropine Nicotinic Muscarinic Atropine

37 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 37 Effects of Atropine on Smooth Muscle ACh AChE Atr Nerve agent present; too much ACh in NMJ

38 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 38 Effects of Atropine on Exocrine Glands Nerve agent present; too much ACh in NGJ Atr ACh AChE Atr

39 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 39 Effects of Atropine on Skeletal Muscle: None! ACh AChE Atr Nerve agent present; too much ACh in NMJ

40 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 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)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”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)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)No direct effects at nicotinic sites (skeletal muscle)

41 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 41 Effects on Heart Rate Qualitatively different between compoundsQualitatively different between compounds AtropineAtropine Initial brief tachycardia pronounced tachycardiaInitial brief tachycardia pronounced tachycardia ScopolamineScopolamine Moderate tachycardia prolonged tachycardiaModerate tachycardia prolonged tachycardia BZBZ Tachycardia x 1-2 days normal rate or mild bradycardiaTachycardia x 1-2 days normal rate or mild bradycardia

42 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 42 Central Effects of Anticholinergics Qualitatively similarQualitatively similar Effective doses vary between compoundsEffective doses vary between compounds Marked confusion results fromMarked confusion results from mg of atropine12-14 mg of atropine 2 mg of scopolamine2 mg of scopolamine 1 mg or less of BZ1 mg or less of BZ ? of Agent 15? of Agent 15

43 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 43 BZ (QNB) 3-Quinuclidinyl benzilate (QNB); Oksilidin3-Quinuclidinyl benzilate (QNB); Oksilidin Developed by a pharmaceutical company during a search for a new GI drugDeveloped 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)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.The only incapacitating agent weaponized by the U.S. Demilitarization of BZ stockpiles began in 1988Demilitarization of BZ stockpiles began in 1988

44 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 44 BZ: Physical Properties Molecular formula C 21 H 23 NO 3 ; MW Molecular formula C 21 H 23 NO 3 ; MW White crystalline solid; m.p C; b.p. 320 CWhite crystalline solid; m.p C; b.p. 320 C Odorless; negligible vapor pressure and volatilityOdorless; negligible vapor pressure and volatility Stable in most materialsStable in most materials Half-life is 3-4 weeks in moist airHalf-life is 3-4 weeks in moist air Very persistent in soil and water and on most surfacesVery persistent in soil and water and on most surfaces

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

46 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 46 BZ: Physiological Data LCt 50 : 200,000 mg min / m 3LCt 50 : 200,000 mg min / m 3 ICt 50 : 112 mg min / m 3ICt 50 : 112 mg min / m 3 Onset of effectsOnset of effects hours after ingestion or inhalation (mean 2 hours; range hours)0.5-4 hours after ingestion or inhalation (mean 2 hours; range hours) Effects may not appear until 36 hours after skin exposureEffects may not appear until 36 hours after skin exposure Duration of effectsDuration of effects hours; dose-dependent (from an ICt 50, severe effects last 36 hours; mild effects persist for 45 hours)72-96 hours; dose-dependent (from an ICt 50, severe effects last 36 hours; mild effects persist for 45 hours)

47 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 47 BZ: Peripheral Effects I Ocular effectsOcular effects Mydriasis (dilated pupils) lasting several daysMydriasis (dilated pupils) lasting several days Paralysis of accommodation impairment of near visionParalysis of accommodation impairment of near vision Oral effectsOral effects Xerostomia (dry mouth); drying of secretions; thirst (“dry as a bone”)Xerostomia (dry mouth); drying of secretions; thirst (“dry as a bone”) Cardiac effectsCardiac effects Heart rate labile (tachycardia x 1-2 days normal or bradycardia); not useful in diagnosisHeart rate labile (tachycardia x 1-2 days normal or bradycardia); not useful in diagnosis Gastrointestinal effectsGastrointestinal effects Decreased motility and decreased secretionsDecreased motility and decreased secretions

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

49 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 49 BZ: Central Effects I Dose-dependent decrease in level of consciousnessDose-dependent decrease in level of consciousness Drowsiness sedation stupor comaDrowsiness sedation stupor coma Perceptual disturbances (“mad as a hatter”)Perceptual disturbances (“mad as a hatter”) IllusionsIllusions Visual hallucinations (realistic, distinct, panoramic, and decreasing in size over time)Visual hallucinations (realistic, distinct, panoramic, and decreasing in size over time) Disturbances in judgment and insightDisturbances in judgment and insight Lack of social restraint profanity and vulgarityLack of social restraint profanity and vulgarity Inability to use perceptual cuesInability to use perceptual cues Denial and confabulationDenial and confabulation

50 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 50 BZ: Central Effects II Attention and memory deficitsAttention and memory deficits Easy distractibilityEasy distractibility Short-term memory lossShort-term memory loss Deficits of expression and comprehensionDeficits of expression and comprehension Slurred, often senseless speechSlurred, often senseless speech Flat, uninflected tone of voiceFlat, uninflected tone of voice PerseverationPerseveration Concrete, semiautomatic speech with colloquialisms, clichés, and profanityConcrete, semiautomatic speech with colloquialisms, clichés, and profanity Handwriting deteriorationHandwriting deterioration Inability to converse meaningfullyInability to converse meaningfully

51 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 51 BZ: Central Effects III Disorientation to time and placeDisorientation to time and place Disrobing, mumbling, and picking (“woolgathering”)Disrobing, mumbling, and picking (“woolgathering”) AtaxiaAtaxia Behavioral labilityBehavioral lability Swings between quiet confusion and combativenessSwings between quiet confusion and combativeness Paranoia as other symptoms are resolvingParanoia as other symptoms are resolving

52 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 52 Psychosocial Aspects Sharing of illusions and hallucinationsSharing of illusions and hallucinations Folie à deuxFolie à deux Folie en familleFolie en famille “Mass hysteria”“Mass hysteria” Similarity to psychogenic conditionsSimilarity to psychogenic conditions May prove hazardousMay prove hazardous

53 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 53 BZ: Clinical Course 1. Onset (induction): 0-4 hours after exposure1. Onset (induction): 0-4 hours after exposure Parasympathetic blockade and mild CNS effectsParasympathetic blockade and mild CNS effects 2. Second phase: 4-20 hours after exposure2. Second phase: 4-20 hours after exposure Stupor (with ataxia and hyperthermia)Stupor (with ataxia and hyperthermia) 3. Third phase: hours after exposure3. Third phase: hours after exposure Delirium (often fluctuating from moment to moment)Delirium (often fluctuating from moment to moment) 4. Fourth phase (resolution): following third phase4. Fourth phase (resolution): following third phase Paranoia; deep sleepParanoia; deep sleep

54 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 54 DDx for Incapacitants I Anticholinergic compounds, indoles, cannabinoids, anxiety reactions, other intoxications (alcohol, bromides, lead, barbiturates)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, vomitingRestlessness, lightheadedness, vertigo, failure to obey orders, confusion, erratic behavior, stumbling or staggering, vomiting AnticholinergicsAnticholinergics 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 sensoriumDryness 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 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 55 DDx for Incapacitants II Indoles (LSD); schizophrenic psychosisIndoles (LSD); schizophrenic psychosis Inappropriate smiling or laughing, irrational fear, distractibility, difficulty expressing self, perceptual distortions, stomach cramps, vomiting, labile changes in HR / BP / mydriasisInappropriate smiling or laughing, irrational fear, distractibility, difficulty expressing self, perceptual distortions, stomach cramps, vomiting, labile changes in HR / BP / mydriasis Cannabinoids (THC)Cannabinoids (THC) Euphoria, relaxation, day-dreaming, unconcerned attitude, easy laughter, orthostatic hypotensionEuphoria, relaxation, day-dreaming, unconcerned attitude, easy laughter, orthostatic hypotension Anxiety reactionAnxiety reaction Tremor, clinging or pleading, crying, alertness, orientation, history of nervousness or immaturity, phobias, paralysis, blindnessTremor, clinging or pleading, crying, alertness, orientation, history of nervousness or immaturity, phobias, paralysis, blindness

56 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 56 Incapacitants and ASBESTOS Agent(s): Type(s) and toxicity (including LD 50 )Agent(s): Type(s) and toxicity (including LD 50 ) State(s): Solid? Liquid? Gas? Vapor? Aerosol?State(s): Solid? Liquid? Gas? Vapor? Aerosol? Body site(s): Where exposed / Route(s) of entry? [absorption]Body site(s): Where exposed / Route(s) of entry? [absorption] Effects: Local? Systemic? [distribution]Effects: Local? Systemic? [distribution] Severity: Mild? Moderate? Severe?Severity: Mild? Moderate? Severe? Time course: Onset of symptoms? Getting better/worse? Prognosis?Time course: Onset of symptoms? Getting better/worse? Prognosis? Other diagnoses: Instead of? [DDx] In addition to?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 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 57 BZ: Treatment Protect yourself!Protect yourself! General supportive therapyGeneral supportive therapy Decontamination with soap and waterDecontamination with soap and water Observation and (in 50-80% of cases) restraintObservation and (in 50-80% of cases) restraint Management of heat stressManagement of heat stress Early evacuationEarly evacuation Specific antidotal therapySpecific antidotal therapy PhysostigminePhysostigmine

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

59 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 59 Physostigmine: Pearls of Therapy Minimally effective during first 4 hours after exposureMinimally effective during first 4 hours after exposure Very effective after 4 hours when administered IM or POVery effective after 4 hours when administered IM or PO Oral dosing requires 1.5 times the dose given IMOral dosing requires 1.5 times the dose given IM Effects last only about minutesEffects last only about minutes Redose frequently or start slow IV infusionRedose frequently or start slow IV infusion Physostigmine does NOT shorten the clinical course of anticholinergic poisoning; relapses will occur if treatment is discontinued prematurelyPhysostigmine does NOT shorten the clinical course of anticholinergic poisoning; relapses will occur if treatment is discontinued prematurely

60 USAMRICD PROTECT, PROJECT, SUSTAIN Incapacitating Agents M_Incaps 60 Physostigmine: Cautions Side effects: Cholinergic (nerve-agent-like)Side effects: Cholinergic (nerve-agent-like) Usually requires only dosage reductionUsually requires only dosage reduction Moderate overdose: Dyspnea and decreased vital capacityModerate overdose: Dyspnea and decreased vital capacity Large overdose: Apnea secondary to respiratory-muscle fatigueLarge overdose: Apnea secondary to respiratory-muscle fatigue ComplicationsComplications Convulsions and severe cardiac dysrhythmias from IV administration if rate is too rapid or if patient is acidotic or hypoxic (IM route safer)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 surgeryDrug interactions during surgery Promethazine may prolong neuromuscular blockadePromethazine may prolong neuromuscular blockade Antimuscarinics may antagonize actionAntimuscarinics may antagonize action Barbiturates may cause addictive bronchospasmBarbiturates may cause addictive bronchospasm Polarizing and nondepolarizing NM blockersPolarizing and nondepolarizing NM blockers

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


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