1. Dr Martin Wilks, Syngenta Crop Protection AG, Basel, Switzerland
Oximes, atropine and diazepam in organophosphate and carbamate poisoning
Dr Martin Wilks, Syngenta Crop Protection AG, Basel, Switzerland

2. Modes of action of the top-selling insecticides/acaricides and their world market share (Nauen, 2002)
Mode of action
1987 (%)
1999 (%)
Change (%)
Acetylcholinesterase 71 51
-20
Voltage-gated Na channel 17 18
+1.4
Nicotinic receptor
1.5 12
+10
GABA-gated Cl channel
5.0
8.3
+3.3
Chitin biosynthesis
2.1
3.0
+0.9
Other
0.5
2.9
+2.4

3. The scale of the problem
Asia: est. 300,000 deaths /year from pesticide poisoning
Est. 200,000 involve ingestion of OPs (and carbamates) (Eddleston and Phillips, 2004, BMJ 328: 32 – 44)
Sri Lanka
17000 admissions
35% ICU
10% Die (20% of symptomatic) 3

4. Outline Review the Mechanism Does the type of compound matter?
Aspects of treatment
Do they need Atropine?
Do they need Decontamination?
Do they need Oximes?
Magnesium, Diazepam, Bicarbonate
Lessons learned

5. Organophosphate Carbamate O(S) II P - O - X O II R1 - NH - C - O - R2
R1,2 = alkyl or aryl groups
X = wide range of branched or substituted groups
R1 = methyl, aromatic or
benzimidazol group
R2 = aromatic or aliphatic
group

6. Acetylcholinesterase and OP
Organophosphate

7. Nicotinic, muscarinic and central syndrome

8. Respiratory failure Central Peripheral Muscarinic Peripheral Nicotinic
Clinical Syndromes
Acute Cholinergic:
Central
Peripheral Muscarinic
Peripheral Nicotinic
Intermediate Syndrome
Delayed peripheral neuropathy
Neurocognitive dysfunction
Respiratory failure 8

9. Acute Cholinergic Syndrome

10. Moat common OP pesticides used in self-poisoning in Sri Lanka
Eddleston M et al Differences between organophosphorus insecticides in human self-poisoning: a prospective cohort study. Lancet Oct 22-28;366(9495):1452-9

11. Chlorpyrifos Dimethoate Fenthion
Number of cases
WHO Toxicity II II II
Formulation % EC % EC % EC
Chemistry Diethyl Dimethyl Dimethyl
Rat oral LD50 (mg/kg)
WHO  Not Given
OSHA
Eddleston M et al Differences between organophosphorus insecticides in human self-poisoning: a prospective cohort study. Lancet Oct 22-28;366(9495):1452-9

12. Relative human toxicity of pesticides in self-poisoning
X symptomatic X
Eddleston M et al Differences between organophosphorus insecticides in human self-poisoning: a prospective cohort study. Lancet Oct 22-28;366(9495):1452-9 12

13. Time to Death Early & late respiratory failure
Hypotensive Shock (Dimethoate)
Iatrogenic 13

14. Chlorpyrifos poisoning

15. Fenthion poisoning

16. Dimethoate poisoning

17. Complicates Assessment of the Evidence
OPs are different
Differing Toxicity
Different Kinetics
Different Clinical Syndromes
Different Response to Antidotes
? Need Different Treatment Responses
Complicates Assessment of the Evidence

18. Sequence of Medical Management
Basic Supportive Care
Does the patient need Atropine ?
Poor air entry into the lungs due to bronchorrhoea and bronchospasm
Bradycardia
Excessive sweating
Small pupils
Hypotension.
Decontamination ?
Oximes?
Adjunctive Treatment ?

19. Atropine – mechanism and endpoints
Which cholinergic effect should be the endpoint?
Pupil size?
Secretions?
Heart rate?
Blood Pressure?
Measurement of peripheral vascular resistance?
Mechanism
Blocks the muscarinic effects due to excess acetylcholine
Competitive inhibitor
Control of symptoms determines the dose by titration

20. Atropine Dose in Organophosphates
Sri Lankan ventilated OP patients who survived require
Mean initial dose of 23.4 mgs.
Maximum initial dose of 75 mg
38 texts with 31 different recommendations
Eddleston M et al .Speed of initial atropinisation in significant organophosphorus pesticide poisoning. J Tox Clin Tox 2004;42(6):865-75

21. Range of times it would take to give adequate doses of atropine (23mg and 75 mg) following the expert advice from each text

22. 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

23. Atropine
Loading
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

24. Decontamination Don’t confuse creating mess with efficacy
Decisions based on risk/benefit analysis

25. Gastric emptying – what happens if you stop?

26. The results of observational data on gastric emptying (GE) in pesticide self-poisoning

27. Eddleston M, et al (2008) Multiple-dose activated charcoal in acute self-poisoning: a randomised controlled trial. Lancet 371:
4632 patients recruited
Overall death rate around 7%, pesticide death rate around 13%
No significant difference between no AC, SDAC and MDAC
Mortality did not differ between groups. Odds ratios:
SDAC vs no AC 1.05 (95% CI: 0.79, 1.40)
MDAC vs no AC 0.93 (95% CI: 0.69, 1.25)
MDAC vs SDAC 0.89 (95% CI 0.66, 1.19)
No difference in rates of ventilation for OP and Carb poisoned patients

28. Therapy with Oximes: Basics3 P O +
EOH P O H C P O + X - H C R O 3 3 X X + H + R O
Inhibition H O N H O R H O 2 2 R O H O O E P O +
EOH + P O H C P O + R + H +
EOH + H C H C 3 3 3 O R O O N R
Reactivation
Spontaneous reactivation
Aging
Worek et al. Biochem Pharmacol. 2004

29. AChE-Status in a Patient with Parathion Poisoning
obidoxime
200
inhibitory activity
150
poison
100 50 25 50 75
100
hours
Patient: A 45-year old, male
Emergency situation: Unconscious, severe signs and symptoms of cholinergic crisis. 1.5 mg of atropine, intubation and initiation of artificial ventilation.
Clinical course: 2 bolus doses of obidoxime together with an atropine infusion at the local hospital. Transfer to the ICU of Technical University, Munich.
The patient recovered uneventfully.
Eyer et al. Toxicol Rev. 2003

30. Oximes Effective protocols not established Variation in use
Zero – 24 grams a day
Intermittent bolus vs continuous infusion
Ineffective against some OPs
Issues of availability/affordability
Pralidoxime
USA $600 / gram
India $9 / gram
Sri Lanka 55 cents / gram

31. ... but do they work?
Buckley et al (2005) Cochrane Database Syst Rev, CD005085
Two published RCTs, one abstract RCT
Insufficient evidence whether oximes are harmful or beneficial
Peter et al (2006) Crit Care Med 34: 502 – 510
Two published RCTs, 5 controlled trials
Oximes either ineffective or harmful
Rahimi et al (2006) Human Exp Toxicol 25: 157 – 162
Six clinical trials
Oximes are not effective and can be dangerous

32. New antidotes, new therapies?
Protect AChE
Cholinesterase inhibitors
Supply AChE Sacrifice
Synthetic and Natural (FFP)
Reduce ACh Release
Magnesium, Clonidine
Protect Receptor
Neuromuscular Blockers
Reduce OP Load
Increase Hydrolase capacity
Multiple Mechanisms
Altering Ph

33. Magnesium Pajoumand A et al (2004) Hum Exp Toxicol 23(12):565-9
Reduces acetylcholine release
Blocks pre-synaptic calcium channels
Central and Peripheral Nervous System
Decrease toxicity in animal models
Pajoumand A et al (2004) Hum Exp Toxicol 23(12):565-9
16 gram continuous infusion MgSO4 for 24 hours
Normal care (oximes and atropine) in both groups
0/11 patients died with magnesium
5/34 control patients
Methodological issues
pseudorandomisation

34. Diazepam
Routinely used in OP poisoning for treatment of agitated delirium and seizures
Diazepam reduces respiratory failure (rats) and cognitive deficit (primates)
Postulate “uncoordinated stimulation of the respiratory centres decreases phrenic nerve output”
Role for peripheral benzodiazepine receptor?

35. Diazepam Synergistic response with anticholinergics
Dickson EW et al Diazepam inhibits organophosphate-induced central respiratory depression. Acad.Emerg.Med ;10(12):1303-

36. Organophosphates and pH
Organophosphate Hydrolase is pH sensitive.
Binding of pralidoxime is pH sensitive.
Acetylcholinesterase
Aging of OP-AChe complex and reactivation.
Organophosphate
In organophosphate poisoning it is known that the function of Organophosphate Hydrolase is pH sensitive. In addition, the binding of pralidoxime is pH sensitive. The function of acetylcholinesterase AChE , aging of OP-AChe complex and reactivation is also pH sensitive.

37. Comparative efficacy of i. v. pralidoxime vs
Comparative efficacy of i.v. pralidoxime vs. NaHCO3 in rats lethally poisoned with OP insecticide (A Wong, Brazil)
5 Groups of 10 rats
DDVP only (no treatment) 0/10
Atropine (17 mg/kg) alone 3/10
Atropine + pralidoxime (1 g/kg) 4/10
Atropine + NaHCO3 (3 meq/kg) 9/10
Atropine + NaCl 0.9% (1.9 ml/kg) 5/10

38. Comparative efficacy of i. v. pralidoxime vs
Comparative efficacy of i.v. pralidoxime vs. NaHCO3 in rats lethally poisoned with OP insecticide (A Wong, Brazil)
D.D.V.P.
Atropine
Atrop. +
Oxime
Bicarb.
NaCl
309.43
462.17
1000
2000
3000
4000
5000
6000
7000
8000
p<0.001 D~B and D~C
p< D~E
N = 10 rats in each group

39. Balali­Mood M. Effect of High Doses of Sodium Bicarbonate in Acute Organophosphorous Pesticide Poisoning. Clinical Toxicology, 43:571­574, 2005
RCT N=30
NaHCO3 pH
5 mEq/Kg over 60 minutes
5-6 mEq/Kg over 24 hours
Length of hospital stay
Controls 5.59 ± 1.97
Treatment 4.33 ± 1.99

40. Some lessons from clinical research
Influence of Initial Care on Mortality
Risk of decontamination
Predictors of Mortality
Pesticide type & Clinical Status
Use Atropine Aggressively but Titrate
The doubling protocol
Reasons for Oxime Failure
Chemical and Kinetic
Implications for where, how and what treatment is delivered
More Large-Scale Randomised Controlled Trials Are Needed, and They Will Be Coming from Sri Lanka

41. Andrew Dawson Michael Eddleston Horst Thiermann Special thanks to
for helpful discussion, permission to use their slides, and many shared drinks