1. Organophosphate Pesticide Poisoning
Bishan Rajapakse
MBChB Otago
Emergency Medicine Advanced Trainee, MPhil Student (ANU),
South Asian Clinical Toxicology Research Collaboration
Sri Lanka

2. 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?

3. Organophosphate Pesticide Poisoning

4. Organophosphate 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

5. 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

6. Poisoning at Anuradhapura Hospital in 2005
Admissions
Death
Case Fatality
Acid 2 0%
Carbamate
105 3 3%
Hydrocarbon 62
Medicine
254 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%

7. Mechanism of OP’s

8. Simplified Acute OP Toxicity
Inactivation of acetylcholinesterase enzyme
Organophosphate

9. Pharmacology of Cholinomimetics according to Katzung
Structure
Simple Alcohols eg edrophonium
Carbamates Eg Neostigmine and Physostigmine (tertiary)
Organophosphates eg Parathion

10. Pharmacokinetics Pharmacodynamics Cholinomimetic Simple Alcohols
Eg 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

11. } Clinical Syndrome Respiratory failure + Death Clinical Syndrome
Acute Cholinergic:
Central
Peripheral Muscarinic
Peripheral Nicotinic
Intermediate Syndrome
OPIDN: Delayed peripheral neuropathy
Neurocognitive dysfunction
+ Death

12. Cholinergic Effects D iarrhoea U rination M iosis
B radycardia, Bronchorrhoea, Bronchospasm
E mesis
L acrimation
S alivation

13. Nicotinic Effects respiratory arrest cardiorespiratory arrest
Respiratory difficulty
respiratory arrest
diaphragmatic weakness
Muscle Weakness
fasiculations
clonus
tremor
Stimulation of sympathetic nervous system
Mydriasis, hypertension, tachycardia
re-entrant dysrhythmias
cardiorespiratory arrest

14. CNS effects Malaise Memory loss Confusion Disorientation Delirium
Seizures
Respiratory centre depression or dysfunction
Coma

15. 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

16. Chronic Effects Organophosphate induced delayed neuropathy (OPIDN)
1-3weeks
Peripheral neuropathy
Axonopathy due to Neuropathy Target Esterases (NTE)
Chronic organophosphate induced neuropsychiatric disorder (COPIND)

17. Management Resuscitation Atropinisation of symptomatic patients
The priorities in management are to:
Resuscitation
Atropinisation of symptomatic patients
Decontamination
Other Treatments - Oximes

18. Antidotes Does treatment affect outcome Atropine Oximes Expensive
Intermediate Syndrome?
OPIDN?
? Dose
? Duration
? Effectiveness

19. Does the patient need atropine?
How much and for how long

20. Scheme of atropinization (endpoints to be reached)5 1 2 3 4 m i n a f t e r s o p d 8 6 A q u P y l g c b h E x v w ( H ) B M z C D S .
> / N
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:

21. Atropine Loading Maintenance Endpoints Withdrawal
Doubling dose regime e.g 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

22. 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
The classic anticholinergic syndrome is described as below:-
Hot as hell
Blind as a bat
Red as a beet
Dry as a bone
Mad as a hatter
Patients may have:-
Elevated BP, red dry skin, dilated pupils, bowel sounds, urinary retention, delirium and convulsion
It can occur with any anticholinergic drugs e.g. cogentin, anticholinergic plants e.g. datura, as well as antihistamines, antidepressant drugs and antipsychotic drugs.

23. Gastrointestinal Decontamination?
Gastrointestinal Decontamination 3

24. Our Decision should depend on a risk/benefit analysis
Nothing
Emesis
Gastric Lavage
Activated Charcoal
Whole bowel irrigation 3

25. Risk of Intervention Aspiration Trauma Electrolyte Abnormalities
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

26. 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:
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:

27. Oximes Ineffective in some situations
Ageing
Variation between organophosphates
Effective protocols not established
Variation in use
Zero – 24 grams a day
Expensive
USA $ / gram
India $6- 9 / gram
Sri Lanka 55 cents / gram
Unlikely to address Non-ACh effects

28. Alternate sites for antidotes
Protect AChE
Supply AChE
Reduce ACh
Protect ACh Receptor
Reduce OP Load
Multiple Mechanisms

29. 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”.

30. 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?

31. Summary OP’s are Indirect Cholinomimetic Effects Treatment
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