Oximes, atropine and diazepam in
organophosphate and carbamate
poisoning
Dr Martin Wilks, Syngenta Crop Protection AG, Basel, Switzerland
Modes of action of the top-selling insecticides/acaricides
and their world market share (Nauen, 2002)
Mode of action
2
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
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
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
4
Organophosphate
Carbamate
O(S)
II
P-O-X
O
II
R1 - NH - C - O - R2
R1
R2
R1,2 = alkyl or aryl groups
X = wide range of
branched or
substituted groups
5
R1 = methyl, aromatic or
benzimidazol group
R2 = aromatic or aliphatic
group
Acetylcholinesterase and OP
Organophosphate
6
Nicotinic, muscarinic and central syndrome
7
Clinical Syndromes
● Acute Cholinergic:
- Central
- Peripheral Muscarinic
- Peripheral Nicotinic
● Intermediate Syndrome
● Delayed peripheral neuropathy
● Neurocognitive dysfunction
8
Respiratory
failure
Acute Cholinergic Syndrome
9
Severity
AChE
(RBC)
Muscarinic
Nicotinic
CNS
Mild
> 40%
nausea, vomiting,
diarrhoea, salivation,
bronchorrhoea and
-constriction,
bradycardia
Moderate
20 - 40% as above, + miosis,
incontinence
fasciculations
(fine muscles)
Severe
< 20%
as above, +
as above, +
fasciculations
coma,
(diaphragm, resp. convulsions
muscles)
headache,
dizziness
as above, +
dysarthria, ataxia
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
10
Chlorpyrifos Dimethoate Fenthion
Number of cases
WHO Toxicity
440
266
100
II
II
II
Formulation
40% EC
40% EC
50% EC
Chemistry
Diethyl
Dimethyl
Dimethyl
Rat oral LD50 (mg/kg)
WHO
OSHA
135
150
Not Given
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
11
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
12
Time to Death
● Early & late
respiratory failure
● Hypotensive Shock
(Dimethoate)
● Iatrogenic
13
Chlorpyrifos poisoning
3000
AChE in vivo
600
mU/ml Plasma
mU/µmol Hb
700
AChE in vitro
500
400
300
200
0
24
48
Time [h]
14
2000
BChE
1500
1000
500
100
ti -5,0
2500
72
96
ti -5,0# 0
24
48
Time [h]
72
96
Fenthion poisoning
500
3000
AChE in vitro
2500
AChE in vivo
mU/ml Plasma
mU/µmol Hb
400
300
200
100
ti -3,7
BChE
1500
1000
500
0
24
48
Time [h]
15
2000
72
96
ti -3,7
0
24
48
Time [h]
72
96
Dimethoate poisoning
3000
500
400
mU/ml Plasma
mU/µmol Hb
AChE in vivo
AChE in vitro
300
200
100
ti -2,2
2000
BChE
1500
1000
500
0
24
48
Time [h]
16
2500
72
96
ti -2,2
0
24
48
Time [h]
72
96
OPs are different
● Differing Toxicity
● Different Kinetics
● Different Clinical Syndromes
● Different Response to Antidotes
● ? Need Different Treatment Responses
Complicates Assessment of the
Evidence
17
Sequence of Medical Management
18
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 ?
Atropine – mechanism and endpoints
● Mechanism
- Blocks the muscarinic
effects due to excess
acetylcholine
● Endpoint
- Which cholinergic effect
should be the endpoint?
- Pupil size?
- Competitive inhibitor
- Control of symptoms
determines the dose by
titration
- 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
20
Range of times it
would take to
give adequate
doses of atropine
(23mg and 75 mg)
following the
expert advice
from each text
21
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
min after first atropine
dose
22
15
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
23
Decontamination
● Don’t confuse creating mess with efficacy
● Decisions based on risk/benefit analysis
24
Gastric emptying –
what happens if you stop?
Case fatality
Anuradhapura Hospital
1998-2002
Case fatality
30
20
10
25
20
02
20
01
20
00
19
99
19
98
0
The results of observational data on gastric emptying
(GE) in pesticide self-poisoning
Case fatality
Anuradhapura Hospital
in and not in RCT
75
Case fatality
No GE (in trial)
GE (NIT)
50
25
0
GCS <14
26
GCS <10
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
27
Therapy with Oximes: Basics
H 3C
RO
H 3C
P O
+
EOH
RO
X
H 3C
P O
RO
H2O
R
P O
O
EOH +
H 3C
+ X-
Inhibition
H2O
HO
RO
EOH +
H 3C
+ H+
X
HON
O E
O E
P O
O E
H 3C
P O
P O
+ R+ + H +
O
RO
N
R
Reactivatio
n
Spontaneous reactivation
Aging
Worek et al. Biochem Pharmacol. 2004
28
AChE-Status in a Patient with Parathion Poisoning
800
200
reactivatability
600
inhibitory activity
150
poison
activity (mU/µmol Hb)
obidoxime
400
100
200
RBC-AChE in vivo
0
50
0
0
25
50
75
hours
100
0
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
29
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
30
55 cents / gram
... 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
31
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
32
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
33
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?
34
Diazepam
● Synergistic response with anticholinergics
- Dickson EW et al Diazepam inhibits organophosphate-induced
central respiratory depression. Acad.Emerg.Med.
2003;10(12):1303-
35
Organophosphates and pH
● Organophosphate Hydrolase is pH sensitive.
● Binding of pralidoxime is pH sensitive.
● Acetylcholinesterase
● Aging of OP-AChe complex and reactivation.
36
Comparative efficacy of i.v. pralidoxime vs. NaHCO3 in
rats lethally poisoned with OP insecticide (A Wong, Brazil)
● 5 Groups of 10 rats
37
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
Comparative efficacy of i.v. pralidoxime vs. NaHCO3 in
rats lethally poisoned with OP insecticide (A Wong, Brazil)
8000
7000
6000
5000
4000
3000
2000
1000
0
7012.12
2611.17
0
D.D.V.P.
p<0.001 D~B and D~C
p<0.01 D~E
309.43
462.17
Atropine
Atrop. +
Oxime
N = 10 rats in each group
38
Atrop. +
Bicarb.
Atrop. +
NaCl
BalaliMood M. Effect of High Doses of Sodium Bicarbonate
in Acute Organophosphorous Pesticide Poisoning. Clinical
Toxicology, 43:571574, 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
- Controls
5.59 ± 1.97
- Treatment 4.33 ± 1.99
39
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
40
Special thanks to
Andrew Dawson
Michael Eddleston
Horst Thiermann
for helpful discussion,
permission to use their
slides, and many shared
drinks
41