Transcript Clinical Trials in Sri Lanka: The challenge and opportunity

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
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
Clinical Syndrome
Acute Cholinergic:
– Central
– Peripheral Muscarinic
– Peripheral Nicotinic
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}
Respiratory
failure
+ Death
Intermediate Syndrome
OPIDN: Delayed peripheral neuropathy
Neurocognitive dysfunction
South Asian Clinical Toxicology Research Collaboration
Cholinergic Effects
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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
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Malaise
Memory loss
Confusion
Disorientation
Delirium
Seizures
Respiratory centre depression or dysfunction
Coma
South Asian Clinical Toxicology Research Collaboration
Intermediate Syndrome
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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
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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
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Endpoints
– Clear chest on auscultation with no wheeze
– Heart rate >80 beats/min
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Withdrawal
– Atropine toxicity
– Clinical Improvement
South Asian Clinical Toxicology Research Collaboration
What if you give too much Atropine ?
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Anticholinergic Syndrome:
–
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–
–
–
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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
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Emesis, Lavage, Charcoal (worse with cathartics)
Trauma
– Oesphageal Injury
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Electrolyte Abnormalities
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Emesis, Lavage, Charcoal
Forced Emesis, Cathartics
Cardiac Arrest
– Toxin induced bradycardia + Vagal Tone
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Induced emesis, Lavage
Cost
South Asian Clinical Toxicology Research Collaboration
Summary of Experimental Evidence
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Ideal settings
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Little benefit in outcomes after 1 hour
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Activated Charcoal is equivalent or better
than emesis or lavage
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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
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Ineffective in some situations
– Ageing
– Variation between organophosphates

Effective protocols not established
– Variation in use
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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
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Reduces acetylcholine release
Blockage pre-synaptic calcium channels
Limited human studies
Clonidine
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Decrease the presynaptic synthesis and release of acetylcholine.
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Central nervous system > peripheral cholinergic synapses
Diazepam
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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