OrganophosphatesNerve Agents/ Pesticides

Baby July M. CuambotAldrine Jay Espinosa

Acetylcholinesterase and OP

Organophosphate

Moat common OP pesticides used in self-poisoning in Sri Lanka

Eddleston M et al Differences between organophosphorus insecticides in human self-poisoning: a prospective cohort study. Lancet. 2005 Oct 22-28;366(9495):1452-9

Malathion

An Organophosphate

Chlorpyrifos Dimethoate Fenthion

Number of cases 440 266 100

WHO Toxicity II II II

Formulation 40% EC 40% EC 50% EC

Chemistry Diethyl Dimethyl Dimethyl

Rat oral LD50 (mg/kg)

WHO 135 150 Not Given

OSHA 97 250 215-245

Eddleston M et al Differences between organophosphorus insecticides in human self-poisoning: a prospective cohort study. Lancet. 2005 Oct 22-28;366(9495):1452-9

OPs are different

• Differing Toxicity• Different Kinetics• Different Clinical Syndromes• Different Response to Antidotes• ? Need Different Treatment Responses

Complicates Assessment of the Evidence

Decontamination• Don’t confuse creating mess with efficacy

• Decisions based on risk/benefit analysis

Overview – Nerve Agents

• Tabun (GA)• 1936 - easiest to manufacture

• Sarin (GB)• 1938 - lethal through inhalation

• Soman (GD) • 1944 - fastest killing, lethal by inhalation

and skin contact

• VX • 1952 - lethal by inhalation and skin

contact

Overview – Pesticides

• Readily available for farm and home use

• Requires only an exterminator’s license

• Common lethal pesticides• TEPP (tetraethyl pyrophosphate)• Parathion• nicotine sulfate• DFP (diisopropyl-phosphorofluoridate)

Overview – Toxicity• Estimated LCt50s by inhalation• 400 mg-min/m3 for Tabun• 100 mg-min/m3 for Sarin• 50 mg-min/m3 for Soman• 10 mg-min/m3 for VX

• Percutaneous LD50s• 1000 mg• 1700 mg• 350 mg• and 6-10 mg, respectively

LD50 of VX Agent, 10 mg of liquid VX, enough to cover about two columns on the Lincoln Memorial on a penny. 

Department of Defense image

Overview – Toxicity

• Full recovery likely after a single mild exposure

• Moderate to severe exposures require treatment for survival

• Repeated exposures are cumulative

Protective Equipment

• Semi-permeable, active carbon protective clothing

• Full-face respirator, appropriate filters• If unavailable: protective gowns,

masks, and gloves can minimize skin exposure

Detection

• Single and three-color detector papers are available to detect liquid nerve agent

• Area detectors / monitoring devices available through emergency management or military contacts

Decontamination

• Nerve agents hydrolyze rapidly in strongly alkaline or chlorinated solutions • Decontaminate victims,

equipment and material

Decontamination

• Dermal exposure:• Absorbing powders • talcum powder, Fullers earth

• Active neutralizing chemicals• chloramine solutions, 5% bleach

• Copious amounts of water can dilute and remove these agents

Decontamination

• Eyes exposure:• Flush well with water for 10-15 minutes

• Safely remove, contain victim clothing• Risk of secondary exposure for

healthcare providers

Signs and Symptoms

• Diagnosis is clinical• Confirmed by agent detection at

exposure scene

• Early signs depend on route of exposure

• Immediate symptoms following inhalation• Delayed as much as 18 hours

Signs and Symptoms

• Muscarinic effects are dominant first• Nicotinic effects follow

• Respiratory distress quickly predominates in moderate to severe exposures

• Ocular signs may come later in the progression of symptoms

• Decreased serum cholinesterase activity can confirm exposure to nerve agents

Signs and Symptoms

• Following a localized skin exposure• Meiosis, usually pinpoint and sometimes

unequal• Frontal headache• Nausea and vomiting• Weakness• Fasciculations or sweating at the

exposure site

Signs and Symptoms

• Severe dermal exposures• Eye pain on focusing and dimmed vision• Rhinorrhea, cough and wheezing• Chest tightness• Generalized muscular twitching or

convulsions• Paralysis• Loss of consciousness• Loss of bladder and bowel control

Signs and Symptoms

• Following a mild inhalation exposure• Meiosis and dimmed vision• Headache• Rhinorrhea• Salivation• Dyspnea and chest tightness

Signs and Symptoms

• Severe inhalation exposures• Chest pain, worsening pulmonary

symptoms• Gastrointestinal disturbances• Muscarinic signs, followed by nicotinic

signs• CNS disturbances• Ultimately: coma, areflexia, Cheyne-

Stokes respiration, convulsions, pulmonary edema, and respiratory and circulatory failure

Treatment• Basic first aid for victims• Assisted ventilation • General supportive measures• Anticholinergic / anticonvulsant agents• Atropine sulfate (antimuscarinic agent) • Titrate atropine until there is a decrease in

bronchial constriction and secretions• Diazepam (10mg IM initially)

MARK I Kit contains 600 mg of 2-pralidoxime chloride (the larger injector) and 2 mg of atropine

(the smaller one). Department of Defense image

Treatment

• Oximes (acetylcholinesterase reactivators)• Relieve the nicotinic symptoms• Pralidoxime chloride and others • Poor CNS penetration

• Pretreatment (prophylaxis)• Pyridostigmine, reversible

anticholinesterase agent, at 30 mg, 3 times daily

Long Term Medical Sequelae

• Full recovery can take up to 3 months • Increased susceptibility may persist up

to 3 months• Reported in animal studies• Persistent paralysis• Organophosphate induced delayed

neuropathy (OPIDN) • Axonal death with demyelination

Environmental Sequelae

• Tabun• Lasts 1-2 days (weather dependant)• Takes 20 times longer than water to

evaporate• Persists in water one day at 20°C, six

days at 5°C

• Sarin• Little persistence • Evaporates as fast as water or kerosene

Environmental Sequelae

• Soman • Lasts 1-2 days (weather dependant)• Takes 4 times longer than water to

evaporate• Thickeners can extend its persistence

• VX • Can persist for weeks to months,

particularly in temperatures near or below 0°C

• Evaporates 1,500 times slower than water

Summary

• Military grade G and V agents • Commercial pesticides• High potential for terrorist • Easily manufactured • Commercially available

• Inhibit tissue cholinesterases at synaptic sites

Summary

• Treatments include • Atropine (anticholinergic) • Diazepam (anticonvulsant)• Acetylcholinesterase reactivator

• High risk of exposure • Prophylactic treatment can be provided

with pyridostigmine