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Warfare AgentsBiological
By: Christian John N. Gabrito and Eugene B. Naval
University of Santo Tomas
Faculty of Pharmacy
Clinical Pharmacy
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Baci l lus
Anthrac is
(Anthrax)
Gram positive spore
forming rod
Toxin production when
protective antigen
combines: Edema factor
Lethal factor
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Incidence of Anthrax (US)
Incidence of naturally-acquired anthrax isextremely rare ( 1-2 cases of cutaneousdisease per year).
GI anthrax is rare, but may occur asexplosive outbreaks associated w/ ingestionof infected animals
Worldwide
incidence is unknown but B.anthracis is present in most of the world
Source: Centers for Disease Control and Prevention
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Mechanism of Toxicity
Inhalational, cutaneous exposure, oringestion
Germination occurs upon ingestion by
the macrophages and transportationto the lymph nodes
Lethal factor: local necrosis and
toxemia Edema factor: fluid accumulation in
the lungs
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Day 2
Site of Detection:
Vesicle Fluid
Blood
Mode of Detection:
Gram stain
ELISA
PCR Chest X-ray
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Day 4
Site of Detection:
Vesicle Fluid
Blood
Mode of Detection:
Gram stain
ELISA
PCR Chest X-ray
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Day 4Site of Detection:
Vesicle Fluid
Blood
Mode of Detection:
Gram stain
ELISA
PCR
Chest X-ray
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Day 7 & 15
Site of Detection:
Vesicle Fluid
Blood
Mode of Detection:
Gram stain
ELISA
PCR Chest X-ray
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Yersinia
Pestis
(Plague)
Gram negative rod-shaped bacterium
Facultative anaerobe
Three main forms: Pnuemonic Septicimic Bubonic plague
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Incidence of Plague in the
US First introduced in the US in 1900.
Between 1900 and 2010, 999 confirmed orprobable human plague cases occurred.
Over 80% of the US plague cases have beenthe bubonic form.
In recent decades, 7 human plague caseseach year (range: 1-17 cases per year)
Worldwide, between 1000 2000 cases/year(WHO)
Source: Center for Disease Control and Prevention
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Mechanism of Toxicicty
Inhalational or bite from an infected
flea
Dissemination through lymphatics,
where bacteria multiple -> lymph node
necrosis
Bacteremia, septicemia, endotoxemia
-> shock, coagulopathy, coma
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Site of Detection: Blood
Cerebrospinal fluid
Lymph node aspirate
Sputum
Mode of Detection:
Fluorescent Antibody
testing
PCR Chest X-ray
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Francisel la
tularensis
(Tularemia)Gram negative
coccobacillus
Fastidious
Facultative intracellular
bacteria
Requires cysteine for
growth
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Incidence of Tularemia
Listed as a rare disease by the Office of
Rare Disease (ORD) of the National Institutes
of Health (NIH). This means that Tularemia affects less than
200,000 people in the US population.
Source: RIGHT DIAGNOSIS from healthgrades Database,
http://www.rightdiagnosis.com/t/tularemia/prevalence.htm
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Mechanism of Toxicicty
Exposure to bodily fluids of infectedanimals or bites of ticks or mosquitoes
Initial focal, suppurated necrosis -> bacterialmultiplication w/in macrophages ->dissemination to lymph nodes, lungs, spleen,liver and kidneys.
Aerosolized bacteria may also be inhaled
Lungs lesions progress to pneumonicconsolidation and granuloma formation ->chronic interstitial fibrosis
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Site of Detection: Blood
Sputum
Mode of Detection:
Biopsy
Direct fluorescent
antibody
Serology
Chest X-ray
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Variola major(Small pox)
DNA virus
Humans are the onlyreservoir
Route of entry Air droplets/aerosols
from highly infectiousviral shedding of skinlesions
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Incidence of Smallpox
The disease was eradicated after asuccessful worldwide vaccination program.
The last case of smallpox in the US was in
1949. The last naturally occurring case was in
Somalia in 1977.
Source: Center for Disease Control and Prevention
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Mechanism of Toxicity
Virus particles reach the LRT cross themucosa -> travel to lymph nodes, wherethey replicate and cause viremia ->further spread in spleen, bone marrowand lymph nodes.
Secondary viremia occurs -> spreads todermis and oral mucosa
Death results from toxemiaassociated with circulating immunecomplexes and soluble variola antigens
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Site of Detection:
Blood
Scabs
Mode of Detection: Light microscopy
Electron microscopy
Cell culture
PCR
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Management
A. Emergency and Supportive measures.
Supportive care treat hypotension
Isolate patients B. Specific Drugs and Antidotes
Antibiotics
Vaccines C. Decontamination
D. Enhanced elimination
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A. Emergency and
Supportive Treat a) hypotension with IV fluids and
vasopressors and b) respiratory failure withassisted ventilation
Isolate patients w/ suspected plague, smallpox or who may be highly contagious. Patientisolation is not needed for suspected anthraxor tularemia.
Drugs causing hypotension: sympatholyticagents, membrane-depressant drugs, fluidloss or third spacing, peripheral venous orarteriolar dilation
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Hypotension
Assessment physiologic derangements(vomiting, diarrhea, bleeding), apparentvolume depletion (vasodilation, arteriolar
dilation, depression of cardiac contractility,dysrhythmias), hypothermia
Complications can cause acute renal tubulenecrosis, brain damage, cardiac ischemia and
also Metabolic acidosis Differential Diagnosis rule out Hypothermia,
Hyperthermia, Fluid loss by gastroenteritis,Blood loss, MI, Sepsis, and Spinal Cord injury
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Hypotension
Treatment
Maintain open airway and assist ventilation
Hypotension assoc. w/ hypothermia will not be
relieved with fluid therapy but by rewarmingthe patient.
IV fluid with NS 10-20ml/kg
Administer dopamine 5-15mcg/kg/min
NaHCO3 for TCA and other channel , Glucagonfor beta receptor antagonist overdose,Propranolol for theophylline, caffeine andmetaproterenol
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B. Specific drugs and
antidotes
1. Antibiotics anthrax, plague andtularemia are susceptible tofluoroquinolones, tetracyclines, and
aminoglycosides Ciprofloxacin 400mg IV q 12 hours
(children: 20-30 mg/kg/day up to 1 bid
Doxycycline 100 mg PO/IV q 12 hours(children 45kg: 2.2mg/kg), Note:discoloration of teeth in children (
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B. Specific drugs and
antidotes
Gentamicin 5 mg/kg IM or IV once daily, orstreptomycin.
Antibiotics should be continued for 60 days
in patients with anthrax.
Post-exposure antibiotic prophylaxis(after exposure to anthrax, plague or
tularemia)
2. Vaccine anthrax and smallpox vaccines
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Decontamination
Remove all potentially contaminated
clothing and wash with patient thoroughly
with soap and water Dilute bleach (0.5%) and ammonia are
effect for cleaning surfaces
All clothing should be cleaned with hotwater and bleach.
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Warfare AgentsChemical(Nerve Agents)
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Nerve agents
Include GA (tabun), GB (sarin), GD (soman)and the other G-series nerve agents.
Named as such because German scientistsfirst synthesized them, beginning with GA in1936.
Volatile liquids making them a serious risk for2 types of exposure dermal contact andinhalation
Potent organophosphorus agents that causeinhibition of acetylcholinesterase andsubsequent excessive muscarinic and nicotinicstimulation.
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Tabun
Solubility = 72 g/L
pKa =
(RS)-Ethyl N,N-Dimethylphosphoramidocyanidate
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Toxicokinetics
Absorption Ocular exposure, oral ingestion, inhalation and
dermal contact
Peak effects are seen within 20-30 mins
Distribution High concentrations in the hypothalamus
Metabolism
Nonspecific enzymes in serum and liver(aliesterases)
Excretion disappear rapidly from the blood, with rapid formation
of
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Sarin
Solubility =
pKa =
(RS)-Propan-2-yl methylphosphonofluoridate
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Toxicokinetics
Adsorption Ocular exposure, oral ingestion, inhalation and
dermal contact
Peak effects are seen within 20-30 mins
Distribution Brain, liver, kidney, and plasma
Metabolism Nonspecific enzymes in serum and liver
(aliesterases)
Excretion
Urinary (metabolic product: IMPA)
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Soman
Solubility = 21g/L
pKa =
3,3-Dimethylbutan-2-yl methylphosphonofluoridate
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Toxicokinetics
Adsorption Ocular exposure, oral ingestion, inhalation and dermal
contact
Peak effects are seen within 20-30 mins
Distribution evenly distributed in the brain with higher levels in the
hypothalamus
Metabolism Nonspecific enzymes in serum and liver (aliesterases)
Excretion stored in body depots and releases toxicity over time
disappear rapidly from the blood, with rapid formation of
hydrolysis products (metabolic product: Pinacolyl phosphonicacid)
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Signs and Symptoms
In general nerve agents producesymptoms of muscarinic and nicotinic
overstimulation:
Excessive salivation and sweating Copious pulmonary secretions
Muscle fasciculations
Respiratory arrest
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Site of Detection
Blood
Mode of Detection:
M8 and M9 paper M256 and M256A1 kits
CBC
BUN
Creatinine
ABG
Chest X-ray
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Warfare AgentsChemical(Vesicants)
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Vesicants (blister agents)
Lewisite combines with thiol moieties in
many enzymes and also contains trivalent
arsenic. Lewisite affects cellular enzyme systems and
damages the mucous membranes, liver,
gallbladder, kidneys, and skin.
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Lewisite
Solubility = 0.5g/L
pKa =
2-chloroethenylarsonousdichloride
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Toxicokinetics
Absorption skin, eyes, and respiratory tract, as well
as by ingestion and via wounds
Distribution
all organs and tissues of the body
Excretion
Urinary
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Signs and Symptoms
Skin blistering Chronic conjunctivitis
Keratitis
Chemical pneumonitis
Chronic bronchitis
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Site of Detection
There are no specific blood or urinelevels that will assist in diagnosis or
management
Mode of Detection: M8 and M9 paper
M256 and M256A1 kits
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Management
A. Emergency and supportive measures
B. Specific drugs and antidotes - Atropine,Pralidoxime, Diazepam, Vesicants, Choking
agents,
C. Decontamination
Physical Removal
Chemical deactivation of chemical agents Oxidation
Hydrolysis
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A. Emergency and supportive
measures
Maintain an open airway and assist
ventilation if necessary. Administer
supplemental oxygen.
Treat hypotension, seizures and coma, if
they occur.
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B. Specific drugs and
antidotes Nerve agents:
Atropine 0.5 2mg IV/IM initially and repeatdose as needed; for persistent wheezing;Note: will reverse muscarinic but not nicotinic
Pralidoxime (2-PAM) specific antidote fororganophosphates, given immediately formuscle weakness and fasciculations as 1-2ginitial bolus dose (20-40mg/kg in children) IVover 5- 10mins.
Diazepam anticonvulsant therapy for theonset of seizures; initial dose is 10 mg IM/IV inadult patients or 0.1 0.3 mg/kg in children.
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B. Specific drugs and
antidotes
Vesicants
British anti-lewisite (BAL) chelating agent
used in the treatment of arsenic, mercuryand lead poisoning, originally was
developed for the treatment of lewisite
exposure.
Topical BAL recommended for eye and skin
exposure to lewisite.
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C. Decontamination
Physical removal removal of clothing,
flushing of exposed skin and eyes;
Chemical deactivation of chemical agents
Oxidation dilute sodium or calcium
hypochlorite (0.5%) can oxidize susceptible
chemicals.
Hydrolysis alkaline hydrolysis ofphosphorus-containing nerve agents; dilute
hypochlorite is slightly alkaline.
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Sarin Poisoning on Tokyo Subway
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INTRODUCTION
On March 20, 1995, terrorists releasedsarin, an organophosphate (OP) nerve gas
at several points in the Tokyo subway
system, killing 11 and injuring more than5,500 people.
Sarin OP anticholinesterase compound
and may include other nerve agents suchas tabun, soman and VX gas.
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Details of the Incident
Nerve gas was released in commutertrains on 3 different Tokyo subway lines.
Sarin was concealed in lunch boxes and
soft-drink containers placed on subwaytrain floors and was later punctured w/
umbrellas before leaving the trains.
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Classifying the Injured
3 categories: a) mild severity principallymobile and had mainly eye problems
related to miosis, rhinorrhea and mild
headache, b) moderate severityimmobile or complained of mod. degree
dyspnea, vomiting, severe headache or
w/ neurologic complications, c) critical-
cardiac or respiratory arrest
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Critical Category
Five were in critical conditions Three patients had cardiopulmonary arrest
(CPA) and 2 were unconscious and had
respiratory arrest Of these 5, three were successfully
resuscitated and able to leave the hospital
while 1 didnt respond to CPR and died withconspicuous miosis and the other died of
irreversible brain damage
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Critical Category
The 3rd patient collapsed and laterresponded to CPR. A generalized
convulsive seizure 1 hr later ceased after
5 mg of Diazpem IV. After initial 1g andsubsequent 0.5g/hr of Pralidoxime iodide
IV, victim regained consciousness.
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Moderate Category
Patients showed sign and symptomsother than eye problems or mildheadache after first 6-hour observation.
Miosis was the most common signpresent while other ophthalmicsymptoms were ocular pain, blurredvision, and visual darkness.
Dyspnea, nausea, vomiting, muscleweakness, coughing, agitation, andfasciculations were common
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Moderate Category
Hospitalized patients were treated with2mg of IV Atropine sulfate and 2g of PAM
after causative agent was confirmed. IV
diazepam for fasciclulations. Miosis was unresponsive to IV atropine
SO4 so mydriatic agents, such as 0.5%
tropicamide and 0.5% phenylephrine,were applied topically
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Mild Category
Mainly with eye problems IV atropine SO4, in doses up to 2mg had
no effect
After administration, patients complainedof palpitations.
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Laboratory Data
A histogram of Serum ChE levels measured
by 5-5; dithiobis (2-nitrobenzoic acid)
method from blood samples taken after
sarin exposure in the 451 hospitalized
patients and outpatients.
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Histogram of Serum ChE levels
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Laboratory Data
Half the patients showed decreased ChElevels and 74% showed decreased ChE
levels.
Those treated with larger doses of PAM(3g or more) than with lower doses (less
than 3g), showed a tendency for serum
ChE levels to improve faster in the groupreceiving larger doses.
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Discussion
Most common signs and symptomsmiosis and miosis-related symptoms such
as visual darkness.
Almost all showed ocular disorders,including marked miosis, ocular pain,
headache especially with near vision, and
blurring vision.
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Discussion
Major respiratory symptoms rhinorrhea,cough and dyspnea.
Severely ill victims respiratory failure
due to CNS involvement, a nicotinic effecton the respiratory muscles and/or
muscarinic effect on the smooth muscle
and secretory glands of the airway,resulting in bronchoconstriction and
excess bronchial secretion.
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Discussion
Attempted to relieve symptoms byadministering IV atropine SO4 but not
effective in counteracting miosis.
Instead, topical application was effectivebut caused side effects such as mydriasis.
Pxs tolerated repeated application of
commercial eye drops with combinedTropicamide and Phenylephrine HCl.
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Discussion
Atropine SO4 to mild ill victims wasadverse.
IV PAM was initiated once causative agent
was distinguished. Principal mode of action of PAM: displace
nerve agent that binds ChE.
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QUESTIONS
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Identification
1. What is the causative agent ofanthrax?
2. What is the causative agent of
tularemia?3. What is the causative agent of small
pox?
4. What is the causative agent ofplague?
5. Give three nerve gas agents? (3 pts.)
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Modified True or False
8. A. Yersinia pestis is Gram positive bacteriaB. It is an aerobic bacterium
9. A. Bacillus anthracis is a gram negativebacteria
B. It is a rod shaped bacteria
10. A. Francisella tularensis is a gram negativebacteria
B. It requires cysteine for growth
11. A. Variola major appears pink on gramstaining
B. Animals can be a reservoir for theirsurvival
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Modified True or False12. A. Tetracycline are effective treatment for small pox
B. Antibiotics are used for 7 days in patients with anthrax
13. A. Skin blistering is a characteristic sign of tabunpoisoning
B. Lewisite produces muscarinic overstimulation
14. A. Lewisite is detected in blood
B. CBC can be used to assist in diagnosing lewisitepoisoning
15. A. Diazepam is used for the inset of seizuresB. Atropine will reverse both muscarinic and nicotinicreceptors
16. A. BAL is used to treat lewisite exposure
B. Pralidoxime is used as an antidote foror ano hos hate oisonin
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Odd man out
17. A. SarinB. Soman
C. Tabun
D. Lewisite
18. A. Anthrax
B. Small pox
C. Tularemia
D. Plague
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Odd man out
19. A. PneumonicB. Septicimic
C. Bacteremic
D. Bubonic
20. A. Ceftriaxone
B. Ciprofloxacin
C. Doxycycline
D. Gentamicin
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Sources
CDC | Bioterrorism. (n.d.). CDC EmergencyPreparedness & Response Site. Retrieved February 21,2013, from http://www.bt.cdc.gov/bioterrorism/
Chemistry of GB (Sarin). (n.d.). Noblis: For the best ofreasons. Retrieved February 21, 2013, fromhttp://www.noblis.org/MissionAreas/nsi/ChemistryofLeth
alChemicalWarfareAgents/Pages/Sarin.aspx Gupta, R. C. (2009). Handbook of toxicology of
chemical warfare agents. London: Academic Press.
Gupta, R. C. (2012). Veterinary toxicology basic andclinical principles(2nd ed.). Oxford: Academic.
Marrs, T. C., Maynard, R. L., & Sidell, F. R.(2007). Chemical warfare agents: toxicology andtreatment(2nd ed.). Chichester, West Sussex, England:Wiley.
Olson, K. (2012). Poisoning & drug overdose (6th ed.).New York: McGraw Hill Medical