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 problemThe 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)
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
O(S)IIP - O - X
R1
R2
O IIR1 - NH - C - O - R2
Organophosphate Carbamate
R1,2 = alkyl or aryl groupsX = wide range of
branched or substituted groups
R1 = methyl, aromatic orbenzimidazol group
R2 = aromatic or aliphaticgroup
6
Acetylcholinesterase and OP
Organophosphate
7
Nicotinic, muscarinic and central syndrome
8
Clinical Syndromes
● Acute Cholinergic:
- Central
- Peripheral Muscarinic
- Peripheral Nicotinic
● Intermediate Syndrome
● Delayed peripheral neuropathy
● Neurocognitive dysfunction
Respiratory failure
9
Acute Cholinergic Syndrome
Severity AChE (RBC)
Muscarinic Nicotinic CNS
Mild > 40% nausea, vomiting, diarrhoea, salivation, bronchorrhoea and -constriction, bradycardia
headache, dizziness
Moderate 20 - 40% as above, + miosis, incontinence
fasciculations (fine muscles)
as above, + dysarthria, ataxia
Severe < 20% as above, + fasciculations (diaphragm, resp. muscles)
as above, + coma, convulsions
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. 2005 Oct 22-28;366(9495):1452-9
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Chlorpyrifos Dimethoate Fenthion
Number of cases 440 266 100
WHO Toxicity II II II
Formulation 40% EC 40% EC 50% EC
Chemistry Diethyl Dimethyl Dimethyl
Rat oral LD50 (mg/kg)
WHO 135 150 Not Given
OSHA 97 250 215-245
Eddleston M et al Differences between organophosphorus insecticides in human self-poisoning: a prospective cohort study. Lancet. 2005 Oct 22-28;366(9495):1452-9
12
Relative human toxicity of pesticides in self-poisoning
X symptomatic
X
X
X
Eddleston M et al Differences between organophosphorus insecticides in human self-poisoning: a prospective cohort study. Lancet. 2005 Oct 22-28;366(9495):1452-9
13
Time to Death
●Early & late respiratory failure
●Hypotensive Shock (Dimethoate)
●Iatrogenic
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Chlorpyrifos poisoning
0 24 48 72 96ti -5,0
100
200
300
400
500
600
700AChE in vivo
AChE in vitro
Time [h]
mU
/µm
ol H
b
0 24 48 72 96ti -5,0#
500
1000
1500
2000
2500
3000
BChE
Time [h]
mU
/ml P
lasm
a
15
Fenthion poisoning
0 24 48 72 96ti -3,7
100
200
300
400
500
AChE in vivo
AChE in vitro
Time [h]
mU
/µm
ol H
b
0 24 48 72 96ti -3,7
500
1000
1500
2000
2500
3000
BChE
Time [h]
mU
/ml P
lasm
a
16
Dimethoate poisoning
0 24 48 72 96ti -2,2
100
200
300
400
500AChE in vivo
AChE in vitro
Time [h]
mU
/µm
ol H
b
0 24 48 72 96ti -2,2
500
1000
1500
2000
2500
3000
BChE
Time [h]m
U/m
l Pla
sma
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OPs are different
● Differing Toxicity
● Different Kinetics
● Different Clinical Syndromes
● Different Response to Antidotes
● ? Need Different Treatment Responses
Complicates Assessment of the Evidence
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Sequence of Medical Management
1. Basic Supportive Care
2. Does the patient need Atropine ?
- Poor air entry into the lungs due to bronchorrhoea and bronchospasm
- Bradycardia
- Excessive sweating
- Small pupils
- Hypotension.
3. Decontamination ?
4. Oximes?
5. Adjunctive Treatment ?
19
Atropine – mechanism and endpoints
● Mechanism
- Blocks the muscarinic effects due to excess acetylcholine
- Competitive inhibitor
- Control of symptoms determines the dose by titration
● Endpoint
- Which cholinergic effect should be the endpoint?
- Pupil size?
- Secretions?
- Heart rate?
- Blood Pressure?
- Measurement of peripheral vascular resistance?
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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)
0 5 10 150
10
20
30
40
min after first atropinedose
2 4 8 16 Atropine requirement
Poor air entry into lungs caused bybronchospasm and bronchorrhoea
Excessive sweating
(Hypotension)
(Bradycardia)
(Miosis)
Atropinization
Clear lungs
Dry axillae
Systol. BP >80 mm HgHeart rate >80/minNo miosis
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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
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Decontamination
● Don’t confuse creating mess with efficacy
● Decisions based on risk/benefit analysis
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Gastric emptying – what happens if you stop?
Case fatalityAnuradhapura Hospital
1998-2002
0
10
20
30
Cas
e fa
talit
y
26
The results of observational data on gastric emptying (GE) in pesticide self-poisoning
Case fatalityAnuradhapura Hospital
in and not in RCT
GCS <14 GCS <100
25
50
75No GE (in trial)
GE (NIT)
Cas
e fa
tali
ty
27
Eddleston M, et al (2008) Multiple-dose activated charcoal in acute self-poisoning: a randomised controlled trial. Lancet 371: 579 - 587
● 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
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Therapy with Oximes: Basics
P O
RO
XCH3
P ORO
X
CH3 O EP O
RO
CH3
O E
P OCH3
O
O E
P O
OH
ROCH3
HON R
P O
RO
ON
R
CH3
+ EOH
+ H+
+ X -
H2O
Inhibition
+ H+R+ +
Aging
H2O
+EOH
Spontaneous reactivation
+EOH
Reactivation
Worek et al. Biochem Pharmacol. 2004
29
AChE-Status in a Patient with Parathion Poisoning
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.
0 25 50 75 1000
200
400
600
800
RBC-AChE in vivo
reactivatability
hours
act
ivity
(m
U/µ
mo
l Hb
)
0 25 50 75 1000
50
100
150
200
inhibitory activity
hours
pois
on
Eyer et al. Toxicol Rev. 2003
obidoxime
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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
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... 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
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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
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Magnesium
● 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
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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. 2003;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.
37
Comparative efficacy of i.v. pralidoxime vs. NaHCO3 in rats lethally poisoned with OP insecticide (A Wong, Brazil)
● 5 Groups of 10 rats
a) DDVP only (no treatment) 0/10
b) Atropine (17 mg/kg) alone 3/10
c) Atropine + pralidoxime (1 g/kg) 4/10
d) Atropine + NaHCO3 (3 meq/kg) 9/10
e) Atropine + NaCl 0.9% (1.9 ml/kg) 5/10
38
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
Atrop. +Bicarb.
Atrop. +NaCl
0309.43 462.17
7012.12
2611.17
010002000300040005000600070008000
p<0.001 D~B and D~Cp<0.01 D~E
N = 10 rats in each group
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Balali Mood M. Effect of High Doses of Sodium Bicarbonate in Acute Organophosphorous Pesticide Poisoning. Clinical Toxicology, 43:571 574, 2005
● RCT N=30
● NaHCO3 pH 7.45-7.55
- 5 mEq/Kg over 60 minutes
- 5-6 mEq/Kg over 24 hours
● Length of hospital stay
- Controls5.59 ± 1.97
- Treatment 4.33 ± 1.99
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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
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Special thanks to
Andrew DawsonMichael EddlestonHorst Thiermann
for helpful discussion, permission to use their slides, and many shared drinks