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

11

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

14

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

17

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?

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)

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

23

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

24

Decontamination

● Don’t confuse creating mess with efficacy

● Decisions based on risk/benefit analysis

25

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

41

Special thanks to

Andrew DawsonMichael EddlestonHorst Thiermann

for helpful discussion, permission to use their slides, and many shared drinks