South Asian Clinical Toxicology Research Collabor Organophosphate Organophosphate Pesticide Pesticide Poisoning Poisoning Bishan Rajapakse MBChB Otago Emergency Medicine Advanced Trainee, MPhil Student (ANU), South Asian Clinical Toxicology Research Collaboration Sri Lanka
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South Asian Clinical Toxicology Research Collaboration
South Asian Clinical Toxicology Research Collaboration
Organophosphate Poisoning in Sri LankaOrganophosphate Poisoning in Sri Lanka
Organophosphate pesticide (OP) poisoning kills 300,000 worldwide– In Sri Lanka these are
mostly impulsive deliberate self-poisoning in young people
South Asian Clinical Toxicology Research Collaboration
Organophosphate Poisoning in Sri LankaOrganophosphate Poisoning in Sri Lanka Case Fatality rates
(CFR)– 10-20% for most– 50-70% for some OP’s
In west CFR– 0.3% from all poisons
Multifactorial– Toxicity of OP’s– Patient transport– Lack of resources– Training
Although less common OP Poisoning is still a problem in West– Occupational exposure– Threat of Chemical warfare
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Poisoning at Anuradhapura Hospital in Poisoning at Anuradhapura Hospital in 20052005
Poison Admissions Death Case Fatality
Acid 2 0 0%
Carbamate 105 3 3%
Hydrocarbon 62 0 0%
Medicine 254 3 1%
Oleander 380 8 2%
OP 408 44 11%
Other Pest. 311 12 4%
Paraquat 59 21 35.50%
Unknown 128 7 5.50%
Un.pesticide 127 13 10%
TOTAL 1836 111 6%
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Mechanism of OP’sMechanism of OP’s
South Asian Clinical Toxicology Research Collaboration
Simplified Acute OP ToxicitySimplified Acute OP Toxicity Inactivation of acetylcholinesterase enzyme
Organophosphate
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Pharmacology of Cholinomimetics Pharmacology of Cholinomimetics according to Katzungaccording to Katzung
StructureSimple Alcohols eg edrophoniumCarbamates Eg Neostigmine and
Physostigmine (tertiary)
Organophosphates eg Parathion
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Cholinomimetic Pharmacokinetics Pharmacodynamics
Simple AlcoholsEg edrophonium
Polar, not fat soluble Electrostatically bind to active site of AChE
(short lived 2-10mins)
Carbamates Tertiary – well absorbed, fat soluble Eg physostigmine
Quaternary- polar, negligible CNS distribution
2 step hydrolysis of to form Carbamoylated enzyme-inhibitor complex (30mins to 6 hours)
- Reversible inhibitors
Organophosphates Variable over 50,000 varieties
Most fat soluble- thus well absorbed and dangerous to humans
(Echothiopate is one of the water soluble varieties) Thiophosphates - need conversion to Oxon form to work
Malathion are metabolised to inactive forms in birds and mammals but not fish
Binding and hydrolysis to form Phosphorylated enzyme-inhibitor complex
Covalent phosphorus-enzyme hydrolyses slowly (hundreds of hours sometimes)-Irreversible inhibitors --May undergo Aging (different rates for different OPs) with no oxime regeneration thereafter
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– Proximal muscle weakness and cranial nerve lesions
– Typically 1-4 days after cholinergic crisis has resolved Prolonged Effects on Nicotinic receptors Primary motor end plate degeneration Clinical importance
– Delayed respiratory failure leads to death if not aware of it or prepared for it
Wadia et. al 1974 :Type II Paralysis, Senanayake and Karalliedde 1987
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Cardiac Arrest– Toxin induced bradycardia + Vagal Tone
Induced emesis, Lavage Cost
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Summary of Experimental EvidenceSummary of Experimental Evidence Ideal settings
Little benefit in outcomes after 1 hour
Activated Charcoal is equivalent or better than emesis or lavage
Position statement: single-dose activated charcoal. J Toxicol Clin Toxicol 1997;35:721-41.
Position statement and practice guidelines on the use of multi-dose activated charcoal in the treatment of acute poisoning. J Toxicol Clin Toxicol 1999;37:731-51.
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OximesOximes Ineffective in some situations
– Ageing– Variation between organophosphates
Effective protocols not established– Variation in use
Zero – 24 grams a day Expensive
USA $30-600 / gram India $6- 9 / gram Sri Lanka 55 cents / gram
Unlikely to address Non-ACh effects
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Alternate sites for antidotesAlternate sites for antidotes
• Protect AChE• Supply AChE• Reduce ACh • Protect ACh
Receptor• Reduce OP Load• Multiple
Mechanisms
South Asian Clinical Toxicology Research Collaboration
Other Treatments under Other Treatments under investigationinvestigation