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USAMRICDPROTECT, PROJECT, SUSTAIN
MEDICAL MANAGEMENT OF CHEMICAL CASUALTIESMEDICAL MANAGEMENT OF CHEMICAL CASUALTIES
NERVE AGENTS&
PRETREAMENT
U.S. ARMY MEDICAL RESEARCH INSTITUTE OF CHEMICAL DEFENSE
NERVE AGENTS
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DEFINITION
• A substance that causes biological effects by inhibiting acetylcholinesterase
• Acetylcholine accumulates
• Effects are due to excess acetylcholine
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EXAMPLES• Carbamates
– Physostigmine (Antilirium)– Neostigmine (Prostigmine)– Pyridostigmine (Mestinon)– Sevin (insecticide)
• Organophosphates– Malathion– Diazinon– “Nerve Agents”
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NERVE AGENTS
• GA (Tabun)
• GB (Sarin)
• GD (Soman)
• GF
• VX
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GA
CH3 CH2 O
O
P
CH3
CH3
N
CN
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GB
CH3
O
OP
CH3
CH3F
CH
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GD
CH3
O
OP
CH3
CH3F
CH C
CH3
CH3
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VX
CH3O
SP CH2N
CH(CH3)2
CH2
CH3CH2O
CH(CH3)2
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HISTORY
• Germany, WW II, nerve agent munitions
• Used by Iraq
• In stockpiles
CONTINUEDCONTINUED
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TERRORIST USE
• Matsumoto, 1994
– 7 deaths
• Tokyo, 1995
– 12 deaths
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PHYSICAL PROPERTIES
• Clear, colorless liquids (when fresh), not “nerve gas”
• Tasteless, most are odorless
• Freeze/melt <0º C
• Boil >150º C
• Volatility GB>GD>GA>GF>VX
• Penetrate skin, clothing
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TOXICITY
LCt50 LD50
mg-min/m3 mg/70kg
GA 400 1,000
GB 100 1,700
GD 70 50
GF 50 30
VX 10 10
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CHOLINESTERASE
• Blood
– Acetyl (red cell, erythrocyte, “true”)
– Butyryl (plasma, pseudo)
• Tissue
– Tissue acetylcholinesterase (at cholinergic receptor sites)
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EXPOSURE INDICATORS
• Inhibition of
• Acetylcholinesterase (RBC)
– most sensitive for nerve agent
• Butyrylcholinesterase (plasma)
– more sensitive for most insecticides
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PHYSIOLOGY: NORMAL• Electrical impulse goes down nerve
• Impulse causes release of neurotransmitter, acetylcholine
• ACh stimulates receptor site on organ
• Causes organ to act
• ACh is destroyed by AChE
• No more organ activity
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Nerve Transmission: Nerve to Nerve
ACh
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Nerve Transmission: Nerve to Nerve
ACh
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Nerve Transmission: Nerve to Nerve
ACh
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Nerve Transmission: Nerve to Skeletal Muscle
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Nerve Transmission: Nerve to Smooth Muscle
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Nerve Transmission: Nerve to Exocrine Gland
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Impulse Termination: The Role of AChE
ACh
AChE
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Impulse Termination: The Role of AChE
ACh
AChE
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PHYSIOLOGY: NERVE AGENT
• Enzyme (AChE) is inhibited
• Does not destroy ACh
• Excess ACh continues to stimulate organ
• Organ overstimulation
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Exposure to Nerve Agent
ACh
AChE
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Exposure to Nerve Agent
ACh
AChE
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Effects on Striated (Skeletal) Muscle
ACh
AChE
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Effects on Smooth and Cardiac Muscle
ACh
AChE
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Effects on Exocrine Glands
ACh
AChE
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ORGANS
• Muscarinic– Smooth muscles– Exocrine glands– Cranial nerves (vagus)
• Nicotinic– Skeletal muscles– Pre-ganglionic nerves
• Both– CNS
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EFFECTS
• Muscarinic– Smooth muscles
• Airways - constrict
• GI tract - constrict
• Pupils - constrict
– Glands• Eyes, nose, mouth, sweat, airways, GI
– Heart, bradycardia (vagal)
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NICOTINIC
• Skeletal muscles
– Fasciculations, twitching, fatigue, flaccid
paralysis
• Pre-ganglionic
– Tachycardia, hypertension
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ACh at Receptors
ACh
ACh ACh
ACh
Nicotinic Nicotinic
Muscarinic Muscarinic
Preganglionicsynapses in ANS
Skeletal muscle
Synapses in CNS
Smooth muscle
Exocrine glands
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HEART RATE
• Muscarinic (vagal) decreases
• Nicotinic (ganglionic) increases
• May be high, low, normal
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CNS
• Acutely, large exposure
– Loss of consciousness
– Seizures
– Apnea
– Death
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CNS
• Acutely, small exposure– Minor CNS effects
• Slowness in thinking and decision making• Sleep disturbances• Poor concentration• Emotional problems• Other minor problems
CONTINUEDCONTINUED
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CNS
• Minor CNS effects
– May last for 3 to 6 weeks
– May follow any exposure
– Not always present
– Very slight, subtle
CONTINUEDCONTINUED
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VAPOR
• Small exposure– Eyes: Miosis; injection; dim,
blurred vision; pain; maybe nausea, vomiting
– Nose: Rhinorrhea
– Mouth: Salivation
– Airways: Shortness of breath
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VAPOR - NOSE and MOUTH
• Runny nose
– Worse than cold or hay fever
– Leaking faucet
• Mouth
– Excessive saliva
– May run out corners
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VAPOR - RESPIRATORY TRACT
• Small exposure– Tight chest
• Moderate exposure– Severe breathing
difficulty
– Gasping, irregular breathing
– Compounded by excessive secretions
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VAPOR - GASTROINTESTINAL
• Exposure to a large but not lethal concentration may cause:
– Nausea, vomiting
– Pain in abdomen
– Diarrhea, involuntary defecation or urination
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VAPOR - CARDIAC
• Heart rate
– Increase or decrease
– Blood pressure - increase
– Not an indicator for care
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VAPOR
• Onset of effects: seconds to minutes
• After removal from vapor
– Effects do not worsen
– May improve
• No late-onset effects
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VAPOR
• Large exposure
• Previously listed effects plus...– Loss of consciousness
– Seizures
– Apnea
– Flaccid paralysis
– Death
CONTINUEDCONTINUED
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LIQUID ON SKIN• Small droplet: local effects
– Sweating, fasciculations
• Medium droplet: systemic effects
– GI
• Large droplet: CNS
– Loss of consciousness, seizures, apnea, flaccid paralysis, death
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LIQUID ON SKIN
• Onset of effects
– Small, medium drop
• As long as 18 hours
– Large, lethal drop
• Usually <30 minutes
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LIQUID ON SKIN
• Onset time, penetration
– Skin site
– Temperature
– Moisture
CONTINUEDCONTINUED
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LIQUID ON SKIN
• Effects may occur despite initial
decontamination
• Effects may worsen
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MIOSIS
• Almost always after vapor
• After liquid on skin:
– Small: no
– Moderate: maybe
– Severe: yes
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MANAGEMENT
• ABCs
• Drugs
• Decontamination
• Supportive
• Not necessarily in that order
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MANAGEMENT
• MOST IMPORTANT
• Protect self
– Protective gear
– Decontaminate casualty
• Protect medical facility
– Decontaminate casualty
CONTINUEDCONTINUED
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DETECTION
• M256A1
• Chemical Agent Monitor
• M8 and M9 paper
• M8A1Automatic Chemical Agent Alarm
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PROTECTIVE POSTURE
MOPP 4!!!!!!
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SKIN DECONTAMINATION
• Early is best, within 1 to 2 minutes– Little benefit after 30 minutes
• Physical removal is best– Forceful flush with water– Stick, dirt, cloth, M291
• Solutions (hypochlorite, etc.)– Detoxify after many minutes
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VENTILATION
• Possibly less need after pyridostigmine
• None forward of Battalion Aid Station
• Very high airway resistance until atropine is given
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ANTIDOTES
• Too much acetylcholine
– Block excess acetylcholine
• Enzyme inhibited
– Reactivate enzyme
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ATROPINE
• A cholinergic blocking drug– An anticholinergic
• Blocks excess acetylcholine
• Clinical effects at muscarinic sites– Dries secretions
– Reduces smooth muscle constriction
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Atropine at Receptors
NicotinicNicotinic
Muscarinic Muscarinic
Atropine
AtropineAtropine
Atropine
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ACh and Atropine at Receptors
ACh
ACh
ACh
Nicotinic
Muscarinic
Atropine
Nicotinic
Muscarinic
Atropine
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ATROPINE• Side effects in unexposed• Starting dose 2 mg or 6 mg• More, 2 mg every 5 to 10 minutes• Until
– Secretions drying– Ventilation improved
• Usual dose: (severe casualty) 15 to 20 mg– 1000s of mgs in insecticide
CONTINUEDCONTINUED
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ATROPINE
• Not for
– Skeletal muscle effects
– Miosis, unless used topically
• Use will cause blurred vision for 24 hours
CONTINUEDCONTINUED
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Action of Atropine on Smooth Muscle
ACh
AChE
AtrAtr
AtrAtr
Atr
Atr
Atr
Atr
Atr
Atr
Atr
Atr
AtrAtr
Atr
Atr
Atr
Atr
Atr
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Effects on Exocrine Glands
ACh
AChE
AtrAtrAtr
Atr
Atr
AtrAtr
Atr
Atr
AtrAtr
AtrAtr
Atr
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Effects on Striated (Skeletal) Muscle: None!
ACh
AChE
Atr
Atr
Atr
Atr
Atr
Atr
Atr
Atr
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OXIMES
• Effects at nicotinic sites
– Increase skeletal muscle strength
• No clinical effects at muscarinic sites
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Action of Pralidoxime Chloride (2-PAM Cl)
AChE NerveAgent
2-PAM Cl
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ACTION OF PRALIDOXIME CHLORIDE(2-PAM Cl)
AChE
2-PAM Cl
Nerve Agent
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OXIMES
• Remove agent from enzyme, unless aging has occurred
• Aging: agent-enzyme complex changes
• Oximes cannot reactivate enzyme
• Aging times: GD 2 min
GB 3 to 4 hours
Others longer
CONTINUEDCONTINUED
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Aging of the Nerve Agent-AChE Complex
AChE NerveAgent
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Introduction of 2-PAM Cl after Aging
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OXIMES
• Other countries have different ones
– England: P2S
– Some European countries: obidoxime
– Israel: TMB4
– Japan: 2-PAMI
CONTINUEDCONTINUED
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2-PAMCL DOSE
• NAAK (MARK I): contains 600 mg
– One or three Combopens; repeat in one hour
• IV: One gram slowly (20 to 30 min)
– Repeat in one hour
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SEIZURES• Without pyridostigmine
– Not prolonged – Anticonvulsant seldom necessary
• Prolonged after pyridostigmine– Possible brain damage from prolonged
seizures– Anticonvulsant needed (diazepam)
• Give diazepam to any severe casualty
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ARRHYTHMIAS
• Initial, transient from agent, atropine
• Terminal after hypoxia
• V-fib if atropine given IV with hypoxia
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RECOVERY
• Severe casualty:
– Without complications, conscious, breathing, in 2 to 3 hours
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RETURN TO DUTY
• Dose-dependent, need dependent
• Could be hours with minor exposure, great need
• Many days after severe exposure
• Consider:– Vision– Minor, subtle mental effects
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LONG TERM
• EEG changes not detected in individuals
– Minor changes detected in an averaged group
– Significance unknown
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MARK I
• Spring powered injectors
– Atropine, 2 mg/0.7 ml
– 2-PAMCl, 600 mg/2 ml
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MARK I AUTO-INJECTOR
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MILD VAPOR EXPOSURE
• Miosis, rhinorrhea
• Rx: Probably none unless rhinorrhea is
severe
• Atropine IM will not help miosis
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MODERATE VAPOR EXPOSURE
• Miosis, rhinorrhea, moderate or severe dyspnea
• Walking and talking
• Rx: 1 MARK I(if dyspnea is quite severe: 2 MARK Is)
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SEVERE VAPOR EXPOSURE
• Conscious or unconscious
• Seizing or post-ictal
• Breathing or not
• Or effects in two or more systems(airway, GI, muscular, CNS)
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SEVERE VAPOR EXPOSURE
• Rx: 3 MARK Is and diazepam ASAP
• Ventilation
• Rx even after cardiac arrest
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MILD LIQUID EXPOSURE
• Localized twitching, sweating
• Rx: 1 MARK I (agent has been absorbed)
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MODERATE SKIN EXPOSURE
• GI effects: vomiting, diarrhea, cramps
• Rx: 1 MARK I
• Watch carefully for 18 hours
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SEVERE SKIN EXPOSURE
• Conscious or unconscious
• Seizing or post-ictal
• Breathing or not
• Or effects in two or more systems(airway, GI, muscular, CNS)
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SEVERE SKIN EXPOSURE
• Rx: 3 MARK Is and diazepam
• Ventilation
• Rx after cardiac arrest
USAMRICDPROTECT, PROJECT, SUSTAIN
MEDICAL MANAGEMENT OF CHEMICAL CASUALTIESMEDICAL MANAGEMENT OF CHEMICAL CASUALTIES
NERVE AGENTSA Case Study From the Tokyo
Subway Incident
U.S. ARMY MEDICAL RESEARCH INSTITUTE OF CHEMICAL DEFENSE
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Tokyo Subway Victim• 35-year-old man• Exposed to sarin during the Tokyo subway attack 20
MAR 95• For approximately 7 minutes after exposure:
– Had tonic-clonic convulsions– Episodes of dyspnea, during which he needed artificial
respiration
• In the hospital emergency room he was comatose and mildly cyanosed
• Both pupils were constricted to 1.5 mm• Had increased oral and nasal secretions and profuse
sweating and vomiting
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Tokyo Subway Victim
• Atropine sulphate and pralidoxime iodide were given intravenously
• The patient began to regain consciousness 8 hours after exposure
• Regained full mobility after 54 hours
• He was, however, disoriented and had an impaired short-term memory
• His electroencephalogram showed mild slowing of alpha activity, intermittent theta bursts, and the development of
delta busts during hyperventilation
– disappeared 3 months after exposure
• CT and MRI imaging showed no focal lesions
• Plasma cholinesterase activity, which was markedly low at 6% of normal levels after exposure, was normal within 3
weeks
• RBC cholinesterase activity was normal after 3 months
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Tokyo Subway Victim• Neuropsychological tests 6 months after exposure showed no global intellectual
impairment or defects in immediate recall
• All his errors on the Mini Mental State were related to recall and temporal orientation
• Performance was particularly impaired on the Logical Memory and Associate Learning scales from the Wechsler Memory Scale-Revised
• Ability to copy the Rey-Osterrieth complex figure was normal (36/36)
• However, when he was asked to reproduce the drawing 3 and 30 minutes later, his performance was worse (18/36 and 3/36, respectively)
• These results suggest a defect in his ability to consolidate new learning and memory
• Furthermore, without confabulation, he showed retrograde amnesia that extended to 70 days before exposure to sarin
• Personality changes characterized by passivity and shallow affect were also evident
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Tokyo Subway Victim• The extent and consequences of brain injury and incapacity due to
nerve gas poisoning in human beings are not understood
• Patient had amnesia similar to that caused by severe acute hypoxia
• Hypoxia may have been a factor in our patient during the first 7 minutes after exposure
• Defects such as retrograde amnesia and character changes might be associated with the direct effects of excess choline
Hatta K et al., Lancet 347:1343, 1996
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PRETREATMENT FOR NERVE AGENT POISONING
U.S. ARMY MEDICAL RESEARCH INSTITUTE OF CHEMICAL DEFENSE
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TERMINAL OBJECTIVE
• Apply principles of pyridostigmine use in enhancing drug therapy for nerve agent intoxication
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WHY?
• Major threat agent: Soman
• Therapy for soman: relatively ineffective
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CARBAMATES
• Transient carbamylation of AChE
• Protects site from OP (nerve agent)
• Carbamylation of only small amount of AChE needed
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Action of Pyridostigmine
Pyridostigmine
AChE
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Action of Pyridostigmine
AChEPyridostigmine
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Action of Pyridostigmine
AChEPyridostigmine
NerveAgent
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Action of Pyridostigmine
AChEPyridostigmine
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Pretreatment
• Pretreatment alone, without therapy provides no benefit
• Pretreatment followed by antidotes after nerve agent: beneficial
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Protective Ratio
• PR =
• PR of 1.0: No effect
• PR of 5.0 desirable for the battlefield
• PR of antidotes against GD: 1.6
LD50 (treated)
LD50 (untreated)
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PR Study in Rhesus Monkeys
GroupGroup LD50 of GDLD50 of GD PRPR
ControlControl 15.3 mcg/kg15.3 mcg/kg 1.0 1.0
Mark I onlyMark I only 25.1 mcg/kg25.1 mcg/kg 1.6 1.6
NAPP + Mark I NAPP + Mark I > 617 mcg/kg> 617 mcg/kg > 40 > 40
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UTILITY OF PRETREATMEN T
• Helpful against: GD, GA
• No added benefit: GB, GF, VX
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BEFORE USE
• Efficacy
• Safety– Short-term
• Side Effects• Performance
– Long-term
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SHORT TERM
• Side effects: <5% of those taking it
• Performance: No decrements in military tasks (including shooting, flying, driving, physical tasks)
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LONG TERM
• Animal studies
• Myasthenia gravis patients – Starting dose usually 60 mg q8h, can go
much higher– Usual course of treatment is years, not weeks
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DOSE REGIMEN
• Dose: 30 mg– Based on RBC-ChE– Inhibition
• Interval: 8 hours– Based on pharmacokinetics of pyridostigmine
• Dosing: 30 mg every 8 hours
• Commander starts, stops use
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WHAT DO YOU SAY IF YOUR COMMANDER ASKS:
• How long after I order pyridostigmine do I have to wait until my troops are protected?
• How soon after I order them to stop taking it can I consider them at risk?
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PYRIDOSTIGMINE: USE
• Mestinon : five decades for myasthenia gravis
• Regonal : anesthesia
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PYRIDOSTIGMINE
• Insignificant binding to plasma proteins
• Bioavailability after oral dose: 8 to 29%
• Elimination: <75% in urine
• Maximal plasma concentration: 1.5 to 2.0 hours
• Elimination half time: 3.5 hours
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PYRIDOSTIGMINE: USE IN GULF WAR
• Compliance unknown
• High incidence (>50%) of side effects
• Most related to pharmacology of drug– GI >50%– GU 5 to 30%
• Medical assistance 1%
• Discontinuance drug <0.1%
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Israeli Study
• Effects of Pyridostigmine on troops in field conditions
– Done under FTX conditions at basic training on 80 troops
– Half of them given pyridostigmine 30 mg q8h or placebo
– Studied before and after 8-day period on drug or placebo
– Study design is double blinded but not crossover
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Results of the Israeli study
• Pyridostigmine-treated soldiers had “mild” GI symptoms in most cases
• Pyridostigmine-treated soldiers had changes on order of 10% in their scores on vertical addition and four-choice (perceptual speed) tasks.
– Other neuropsychiatric parameters were unaffected.
• The two groups had no difference in their endocrine or stress tests including cortisol
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Conclusions:
• Soldiers did as well functionally with as without pyridostigmine
• Functional significance of neuropsychiatric changes is unclear• Commanders and their troops had no complaints and those
with mild changes were functionally unaware of them.
Limitation:No systematic long-term follow-up
–MAJ Givoni Israeli Defence Force
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PYRIDOSTIGMINE
• After pretreatment, nerve agent, antidotes: breathing and seizures continue
• Potential brain damage
• Anticonvulsant (diazepam) needed (10 mg via auto-injector)
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Effects of Long-term Administration
• In vitro and in vivo evidence of myopathy
• Complaints of weakness, fatigue, etc.
• U.K. 60-day study
• U.S. doctrine does not advocate long-term use
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PYRIDOSTIGMINE: SUMMARY
• Pretreatment, not a substitute for treatment
• “Hides” or protects a fraction of AChE (creates a “reserve force”
• Increases the amount of nerve agent a person can be exposed to and survive
• Causes predictable side effect profile
• Does not interfere with military function
USAMRICDPROTECT, PROJECT, SUSTAIN
SUMMARYANY QUESTIONS?
MEDICAL MANAGEMENT OF CHEMICAL CASUALTIESMEDICAL MANAGEMENT OF CHEMICAL CASUALTIES
U.S. ARMY MEDICAL RESEARCH INSTITUTE OF CHEMICAL DEFENSE