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Organophosphate Pesticide Poisoning Bishan Rajapakse MBChB Otago Emergency Medicine Advanced Trainee, MPhil Student (ANU), South Asian Clinical Toxicology Research Collaboration Sri Lanka South Asian Clinical Toxicology Research Collaboration 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 Poisoning South Asian Clinical Toxicology Research Collaboration Organophosphate Poisoning in Sri Lanka Organophosphate pesticide (OP) poisoning kills 300,000 worldwide – In Sri Lanka these are mostly impulsive deliberate selfpoisoning in young people South Asian Clinical Toxicology Research Collaboration Organophosphate 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 South Asian Clinical Toxicology Research Collaboration Poisoning at Anuradhapura Hospital in 2005 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% South Asian Clinical Toxicology Research Collaboration Mechanism of OP’s South Asian Clinical Toxicology Research Collaboration Simplified Acute OP Toxicity Inactivation of acetylcholinesterase enzyme Organophosphate South Asian Clinical Toxicology Research Collaboration Pharmacology of Cholinomimetics according to Katzung Structure Simple Alcohols eg edrophonium Carbamates Eg Neostigmine and Physostigmine (tertiary) Organophosphates eg Parathion South Asian Clinical Toxicology Research Collaboration Cholinomimetic Pharmacokinetics Pharmacodynamics Simple Alcohols 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 enzymeinhibitor 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 enzymeinhibitor 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 Eg edrophonium South Asian Clinical Toxicology Research Collaboration Clinical Syndrome Clinical Syndrome Acute Cholinergic: – Central – Peripheral Muscarinic – Peripheral Nicotinic } Respiratory failure + Death Intermediate Syndrome OPIDN: Delayed peripheral neuropathy Neurocognitive dysfunction South Asian Clinical Toxicology Research Collaboration Cholinergic Effects D iarrhoea U rination M iosis B radycardia, Bronchorrhoea, Bronchospasm E mesis L acrimation S alivation South Asian Clinical Toxicology Research Collaboration Nicotinic 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 South Asian Clinical Toxicology Research Collaboration CNS effects Malaise Memory loss Confusion Disorientation Delirium Seizures Respiratory centre depression or dysfunction Coma South Asian Clinical Toxicology Research Collaboration Intermediate 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 South Asian Clinical Toxicology Research Collaboration Chronic Effects Organophosphate induced delayed neuropathy (OPIDN) 1-3weeks Peripheral neuropathy Axonopathy due to Neuropathy Target Esterases (NTE) Chronic organophosphate induced neuropsychiatric disorder (COPIND) South Asian Clinical Toxicology Research Collaboration Management The priorities in management are to: Resuscitation Atropinisation of symptomatic patients Decontamination Other Treatments - Oximes South Asian Clinical Toxicology Research Collaboration Antidotes Atropine Oximes – Expensive Does ? Dose ? Duration ? Effectiveness treatment affect outcome – Intermediate Syndrome? – OPIDN? South Asian Clinical Toxicology Research Collaboration Does the patient need atropine? How much and for how long South Asian Clinical Toxicology Research Collaboration Scheme of atropinization (endpoints to be reached) 2 4 8 16 40 Atropine requirement Atropinization Poor air entry into lungs caused by bronchospasm and bronchorrhoea Clear lungs Excessive sweating Dry axillae (Hypotension) Systol. BP > 80 mm Hg Heart rate > 80/min No miosis 30 20 (Bradycardia) 10 (Miosis) 0 0 5 10 15 min after first atropine dose 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. South Asian Clinical Toxicology Research Collaboration Atropine 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 South Asian Clinical Toxicology Research Collaboration 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 South Asian Clinical Toxicology Research Collaboration Gastrointestinal Decontamination South Asian Clinical Toxicology Research Collaboration Our Decision should depend on a risk/benefit analysis Nothing Emesis Gastric Lavage Activated Charcoal Whole bowel irrigation South Asian Clinical Toxicology Research Collaboration Risk of Intervention Aspiration – Impaired GCS + Unprotected Airway Emesis, Lavage, Charcoal (worse with cathartics) Trauma – Oesphageal Injury Electrolyte Abnormalities Emesis, Lavage, Charcoal Forced Emesis, Cathartics Cardiac Arrest – Toxin induced bradycardia + Vagal Tone Induced emesis, Lavage Cost South Asian Clinical Toxicology Research Collaboration Summary 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 Oximes Ineffective in some situations – Ageing – Variation between organophosphates Effective protocols not established – Variation in use Zero – 24 grams a day Expensive USA India Sri Lanka $30-600 / gram $6- 9 / gram 55 cents / gram Unlikely to address Non-ACh effects South Asian Clinical Toxicology Research Collaboration Alternate 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 investigation 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…. 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 Summary 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 South Asian Clinical Toxicology Research Collaboration