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 self-
poisoning 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  Although less common OP
– Patient transport Poisoning is still a problem
in West
– Lack of resources – Occupational exposure
– Training – 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
SimpleAlcohols eg edrophonium
Carbamates Eg Neostigmine and
Physostigmine (tertiary)
Organophosphates eg Parathion

South Asian Clinical Toxicology Research Collaboration

Cholinomimetic Pharmacokinetics
Simple Alcohols Polar, not fat soluble
Eg edrophonium
Carbamates Tertiary – well absorbed, fat soluble
Eg physostigmine
Quaternary- polar, negligible CNS
distribution
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
South Asian Clinical Toxicology Research Collaboration
Pharmacodynamics
Electrostatically bind to active
site of AChE
(short lived 2-10mins)
2 step hydrolysis of to form
Carbamoylated enzyme-
inhibitor complex (30mins to 6
hours)
- Reversible inhibitors
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
 Clinical Syndrome
 Clinical Syndrome

}
 Acute Cholinergic:
– Central
– Peripheral Muscarinic
Respiratory
failure
– Peripheral Nicotinic
 Intermediate Syndrome + Death
 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 ? Dose
 Oximes ? Duration
?
– Expensive Effectiveness
 Does 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 Atropine requirement Atropinization

Poor air entry into lungs caused by Clear lungs

40
bronchospasm and bronchorrhoea

Excessive sweating Dry axillae

30
(Hypotension) Systol. BP >
80 mm Hg
20
(Bradycardia) Heart rate >
80/min
10 (Miosis) No 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
 GastricLavage
 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
 Emesis, Lavage, Charcoal
 Electrolyte Abnormalities
 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 $30-600 / gram
 India $6- 9 / gram
 Sri Lanka 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