Use of oximes in the management of organophosphorus pesticide poisoning Michael Eddleston South Asia

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Use of oximes in the management of
organophosphorus pesticide poisoning Michael
EddlestonSouth Asian Clinical Toxicology
Research Collaboration,Centre for Tropical
Medicine,Nuffield Department of Medicine,
University of Oxford.Dept of Clinical
Medicine, University of Colombo,Sri
Lanka.Funded by the
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PralidoximePyridine-2-aldoximeQuarternary
ammonium salt discovered by Wilson 1955Four
salts chloride (2-Pam, Mw 173), mesilate (Mw
232) metilsulfate (Mw 249), iodide (Mw
264), Renal excretion (85 in urine 24hrs after
bolus dose)VD 0.6 L/kgT ½a 4.2 minsT ½b
75 mins (Some papers suggest that PK is altered
in patients)
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Wilsons work in early 1950s BBA 1955
Nicotinohydroxamic acid methiodide
2 pyridine aldoxime
2 pyridine aldoxime methiodide 2 pralidoxime
methiodide, 2-PAM
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Wilsons work in early 1950s BBA 1955
LuH6
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PralidoximePyridine-2-aldoximeQuarternary
ammonium salt discovered by Wilson 1955Four
salts chloride (Mw 173), iodide (Mw 264),
metilsulfate (Mw 249), mesilate (Mw
232)Renal excretion (85 in urine 24hrs after
bolus dose)VD 0.6 L/kgT ½a 4.2 minsT ½b
75 mins (Some papers suggest that PK is altered
in patients)
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Effect of thiamine coadministration on
pralidoxime PK

• Josselson 1978
• Comparison of PAM chloride 5 mg/kg over 2 min
  alone vs
• PAM chloride constant infusion of thiamine 100
  mg/hr

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Oxime pharmacology
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PralidoximeFirst used clinically by Namba in
1956Most textbooks now recommend a regimen
of 1g over 5-20 mins, repeated after 3-8 hrs.
Commonly given for just 24 hrs.However, many
Asian clinicians doubt its effectivenessThe
World Health Organization responds that
pralidoxime should be given.But what is the
clinical trial evidence?
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What is the clinical evidence for oximes use? 1

• 1991 Senanayake, Peradeniya, SL.
• Found no difference in OP poisoning fatality
  rate during 6 months when pralidoxime was
  available compared to a 6 month period when it
  was not available (when each patient received 1g
  q6h for 1 day).
• WHO response too low a dose. But no trials to
  support this view.

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PAM 20 mg/L 75 µMol
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What is the clinical evidence for oximes use? 2

• 1992 Samuel, Vellore, India.
• Compared 1g bolus pralidoxime with a 12g
  infusion over 4 days in 72 patients. Found
  non-significant increase in death and ventilation
  requirement in patients receiving the infusion.
• 1993 Cherian, Vellore, India.
• Compared 12g infusion over 3 days with placebo
  in 110 patients. Found significant increase in
  death, intermediate syndrome, and ventilation
  requirements in patients receiving pralidoxime
• WHO uncertain methodology, no loading dose

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1993 Cherian RCTCompared 12g PAM given over 3
days (estimated 3.7mg/kg for a 45kg patient) with
saline placebo in 110 patients PAM increased
mortality AR 16/55 29 with PAM vs. 3/55 5
with placebo Relative risk 5.3, 95 CI 1.7 to
17.3PAM increased requirement for ventilation
AR 36/55 67 with PAM vs. 22/55 40 with
placebo Relative risk 1.7, 95 CI 1.1 to 2.4
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High dose PAM PK in RCT 2 from
Vellore (0.16g/hr infusion without bolus in 50kg
person)
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Comparison of PAM and obidoxime
Eyer 2003, Toxicol Rev
100 µMol
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100 nMol paraoxon
Eyer 2003, Toxicol Rev
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• There may also be differences between OPs in how
  they respond to oximes

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diEthyl vs. diMethyl OPs
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Oxime pharmacology
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Summary

• Half-life of reaction 1 - Inhibition
• - Milliseconds for both diMethyl and diEthyl OPs
• Half-life of reaction 2 - Spontaneous
  reactivation
• 1 hr for diMethyl
• 30hrs for diEthyl
• Half-life of reaction 2 - Ageing
• 3hrs for diMethyl
• 33hrs for diEthyl

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Conclusions

• Inhibition is very fast, reactivation much
  slower.
• diMethyl OPs reactivate faster than diEthyl OPs.
• But oximes speed up reactivation for both.
• Ageing also occurs faster with diMethyl OPs
  reactivation being no longer possible after 4
  half-lives (12hrs) and severely limited after 1-2
  half-lives (3-6hrs).
• Ageing takes longer with diEthyl OPs oximes may
  therefore work for up to 130hrs (5 days), and be
  very effective after 1 half-life (gt 1 day).

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• Do we see any evidence of this variable response
  clinically?

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Organophosphorus pesticide poisoning
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Chlorpyrifos poisoning
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Fenthion poisoning
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Dimethoate poisoning
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• Have we got the dose wrong for dimethoate?

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Dimethoate poisoning in Munich
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Profenofos
Prothiofos
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Profenofos poisoning
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Current view of OPs in relation to Rx

• Diethyl OPs - toxic but responsive to PAM
• Dimethyl OPs - less toxic but less responsive
• S-linked OPs - less toxic but not responsive
• Pralidoxime seems to work for some OPs, not for
  others

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• An RCT of high-dose pralidoxime in acute
  symptomatic organophosphorus pesticide
  self-poisoning
• Patients all patients (gt13yrs, not pregnant)
  with a
• history of OP self-poisoning and symptoms/
• signs consistent with Dx.
• Outcome vital status at discharge
• Power to detect a reduction in all-cause
  mortality
• from 25 to 19, 750 patients must be
• recruited to each arm of the study (1500 in
  total)
• Rx - saline placebo bolus and infusion.
• - bolus of 2g pralidoxime chloride followed by
  an
• infusion of 500mg/hr for up to 7 days.

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Chlorpyrifos poisoning
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Parathion reactivation
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• Variation between OPs might be the reason why
  earlier trials did not find benefit from
  pralidoxime

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• Another reason may be time to onset of poisoning
• If the patient becomes severely ill SOON after
  ingestion, they may well lose consciousness and
  aspirate the pesticide, or stop breathing and
  suffer hypoxic brain damage, before hospital
  admission.
• In this case, patients will die in hospital from
  aspiration pneumonia or hypoxic brain damage.
• Provision of antidotes including pralidoxime will
  then be irrelevant.

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Lancet 368 2136

• A recent study carried out by S Pawar and
  colleagues in Baramati, Maharashtra, suggests
  that very high doses of pralidoxime iodide may
  benefit many patients with diEthyl and diMethyl
  OP poisoning who present early
• RCT of 200 patients
• All received 2g loading dose,
• then for 48hrs
• either 1g infused over 1 hr every 1 hr
• or 1g infused over 1 hr every 4 hrs
• followed by 1g every 4 hours until off ventilator

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Pawar - usual dose arm
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Pawar - high dose arm
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Results

• Case fatality 8 in control group
• 1 in high dose group
• Ventilation median time 10 hrs in control group
• median time 3 hrs in high dose group
• Interestingly, seemed to work for both dimethoate
  (diMethyl OP) and chlorpyrifos (diEthyl OP).
• The patients seem to have been moderately
  poisoned, with severely poisoned patients
  excluded.
• ? Valid for severely poisoned patients?

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Different experiences of oxime use

• Baramati good effect
• using PAM for all
  moderately ill cases
• CMC Vellore no clinical benefit/adverse effect
• not using PAM
  anymore
• yet excellent CFR in ICU (8)
• Sri Lanka little clinical benefit
• using bolus doses of
  PAM
• high CFR in ICU (40)

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Different experiences of oxime use

• Baramati early presentation (median
  2hrs)
• excellent
  supportive care
• benefit for both
  diM and diE OPs
• CMC Vellore late presentation (median
  10-12hrs)
• excellent
  supportive care
• most patients
  have taken diM OPs
• Sri Lanka early presentation
  (median3-4hrs)
• very poor
  supportive care
• biochemical
  effect only with diE OPs

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Conclusions

• The ideal regimen is likely to involve high doses
  and a bolus dose followed by an infusion
• However
• the evidence base for pralidoxime use is weak
• There is variable biochemical response to oximes
  by AChE inhibited by different OPs.
• Some OPs may not respond at all
• The time to presentation will affect whether
  pralidoxime is effective