South Asian Clinical Toxicology Research Collaboration
OrganophosphateOrganophosphate PesticidePesticide
PoisoningPoisoningOrganophosphateOrganophosphate PesticidePesticide
PoisoningPoisoning
Bishan RajapakseMBChB Otago
Emergency Medicine Advanced Trainee, MPhil Student (ANU), South Asian Clinical Toxicology Research Collaboration
Sri Lanka
Bishan RajapakseMBChB Otago
Emergency Medicine Advanced Trainee, MPhil Student (ANU), South Asian Clinical Toxicology Research Collaboration
Sri Lanka
South Asian Clinical Toxicology Research Collaboration
The Case….The Case…. Picture yourself in Anuradhapura hospital Sri
Lanka – ED/ Medical SHO Ward 6 , teaming with patients…. Charge Sister tells you there is a sick patient
– 36yo F– Taken 100mls of Dimethoate after a domestic
argument There’s nowhere to run, or hide…. So you see
the patient – what do you do?
South Asian Clinical Toxicology Research Collaboration
Organophosphate Pesticide Organophosphate Pesticide PoisoningPoisoning
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
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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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+ Death
Clinical Syndrome Acute Cholinergic:
– Central– Peripheral Muscarinic– Peripheral Nicotinic
Intermediate Syndrome OPIDN: Delayed peripheral neuropathy Neurocognitive dysfunction
Clinical SyndromeClinical Syndrome
Respiratory failure
Respiratory failure}}
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Cholinergic EffectsCholinergic Effects
D iarrhoea U rination M iosis B radycardia, Bronchorrhoea, Bronchospasm E mesis L acrimation S alivation
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Nicotinic EffectsNicotinic Effects Respiratory difficulty
– respiratory arrest– diaphragmatic weakness
Muscle Weakness– fasiculations– clonus– tremor
Stimulation of sympathetic nervous system– Mydriasis, hypertension, tachycardia– re-entrant dysrhythmias
– cardiorespiratory arrest
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CNS effectsCNS effects Malaise Memory loss Confusion Disorientation Delirium Seizures Respiratory centre depression or dysfunction Coma
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Intermediate SyndromeIntermediate Syndrome Delayed Respiratory Failure
– 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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Chronic EffectsChronic Effects Organophosphate induced delayed
neuropathy (OPIDN) 1-3weeks Peripheral neuropathy Axonopathy due to Neuropathy Target Esterases
(NTE)
Chronic organophosphate induced neuropsychiatric disorder (COPIND)
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ManagementManagementThe priorities in management are to:
Resuscitation Atropinisation of symptomatic patients
Decontamination Other Treatments - Oximes
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AntidotesAntidotes Atropine Oximes
– Expensive Does treatment affect outcome
– Intermediate Syndrome?
– OPIDN?
? Dose ? Duration ? Effectiveness
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Does the patient need Does the patient need atropine?atropine?
How much and for how long
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Scheme of atropinization Scheme of atropinization (endpoints to be reached)(endpoints to be reached)
Eddleston M, Buckley NA, Mohamed F, Senarathna L, Hittarage A, Dissanayake W, Azhar S, Sheriff MHR, Dawson AH. Speed of initial atropinisation in significant organophosphorus pesticide poisoning - a comparison of recommended regimens. Journal of Toxicology – Clinical Toxicology 2004;6:865-875.
0 5 10 150
10
20
30
40
min after first atropinedose
2 4 8 16 Atropine requirement
Poor air entry into lungs caused bybronchospasm and bronchorrhoea
Excessive sweating
(Hypotension)
(Bradycardia)
(Miosis)
Atropinization
Clear lungs
Dry axillae
Systol. BP >80 mm HgHeart rate >80/minNo miosis
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AtropineAtropine Loading
– Doubling dose regime e.g. 2 4 8 16 mgs every 5 minutes
Maintenance– Continuous infusion < 3mg/hr– 10-20% of loading dose/hour
Endpoints– Clear chest on auscultation with no wheeze– Heart rate >80 beats/min
Withdrawal– Atropine toxicity– Clinical Improvement
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What if you give too much Atropine ?What if you give too much Atropine ? Anticholinergic Syndrome:
– Hot as hell
– Blind as a bat
– Red as a beet
– Dry as a bone
– Mad as a hatter
A sensitive indicator for ingestion, but poor predictor for toxicity.
Full syndrome is rare
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Gastrointestinal DecontaminationGastrointestinal Decontamination
?
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Our Decision should depend Our Decision should depend on a risk/benefit analysison a risk/benefit analysis
Nothing Emesis Gastric Lavage Activated Charcoal Whole bowel irrigation
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Risk of InterventionRisk of Intervention Aspiration
– Impaired GCS + Unprotected Airway Emesis, Lavage, Charcoal (worse with
cathartics) Trauma
– Oesphageal Injury Emesis, Lavage, Charcoal
Electrolyte Abnormalities Forced Emesis, Cathartics
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.
South Asian Clinical Toxicology Research Collaboration
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
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Other Treatments under Other Treatments under investigationinvestigation
Magnesium Reduces acetylcholine release Blockage pre-synaptic calcium channels Limited human studies
Clonidine Decrease the presynaptic synthesis and release of acetylcholine. Central nervous system > peripheral cholinergic synapses
Diazepam Diazepam reduces respiratory failure (rats) and cognitive
deficit (primates) Postulate “uncoordinated stimulation of the respiratory centres
decreases phrenic nerve output”.
South Asian Clinical Toxicology Research Collaboration
The Case….The Case…. Picture yourself in Anuradhapura hospital Sri
Lanka – ED/ Medical SHO Ward 6 , teaming with patients…. Charge Sister tells you there is a sick patient
– 36yo F– Taken 100mls of Dimethoate after a domestic
argument There’s nowhere to run, or hide…. So you see
the patient – what do you do?
South Asian Clinical Toxicology Research Collaboration
SummarySummary OP’s are Indirect Cholinomimetic
– Block AChE, prolonged duration of ACh in synapse
Effects– Muscarinic, Nicotinic, CNS– Respiratory failure and Death result from this
Treatment– ABC’s, Atropine, Decontaminate, Oximes
Important also in West