Organophosphate Wiki Wilks by xiaoyounan

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									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             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



2
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)                        O
             II                          II
       R1
             P-O -X            R1 - NH - C - O - R2
       R2


R1,2 = alkyl or aryl groups   R1 = methyl, aromatic or
X = wide range of                  benzimidazol group
       branched or            R2 = aromatic or aliphatic
       substituted groups          group

 5
 Acetylcholinesterase and OP

Organophosphate




 6
Nicotinic, muscarinic and central syndrome




7
Clinical Syndromes

    ● Acute Cholinergic:
      - Central
      - Peripheral Muscarinic         Respiratory
      - Peripheral Nicotinic            failure
    ● Intermediate Syndrome


    ● Delayed peripheral neuropathy
    ● Neurocognitive dysfunction


8
    Acute Cholinergic Syndrome



       Severity   AChE     Muscarinic               Nicotinic        CNS
                  (RBC)
       Mild       > 40%    nausea, vomiting,                         headache,
                           diarrhoea, salivation,                    dizziness
                           bronchorrhoea and
                           -constriction,
                           bradycardia

       Moderate   20 - 40% as above, + miosis,      fasciculations   as above, +
                           incontinence             (fine muscles)   dysarthria, ataxia
       Severe     < 20%                             as above, +       as above, +
                                                    fasciculations    coma,
                                                    (diaphragm, resp. convulsions
                                                    muscles)




9
 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                     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



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
                  700
                                        AChE in vivo                        2500




                                                             mU/ml Plasma
                  600
     mU/µmol Hb




                  500
                                        AChE in vitro                       2000
                                                                                         BChE
                  400                                                       1500
                  300
                                                                            1000
                  200
                                                                             500
                  100


          ti -5,0       0   24     48       72          96            ti -5,0# 0   24     48    72   96
                             Time [h]                                               Time [h]




14
Fenthion poisoning




                  500                                                   3000
                                    AChE in vitro                       2500
                  400
                                    AChE in vivo




                                                         mU/ml Plasma
     mU/µmol Hb




                                                                        2000
                  300                                                                    BChE
                                                                        1500
                  200
                                                                        1000

                  100                                                    500


        ti -3,7         0   24     48     72        96             ti -3,7     0   24     48    72   96

                             Time [h]                                               Time [h]




15
Dimethoate poisoning




                  500                                                  3000
                                    AChE in vivo
                                                                       2500
                  400




                                                        mU/ml Plasma
                                   AChE in vitro
     mU/µmol Hb




                                                                       2000
                  300                                                                   BChE
                                                                       1500
                  200
                                                                       1000
                  100                                                   500


      ti -2,2           0   24     48      72      96          ti -2,2        0   24     48    72   96
                             Time [h]                                              Time [h]




16
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 ?


18
 Atropine – mechanism and endpoints


     ● Mechanism                  ● Endpoint

       - Blocks the muscarinic      - Which cholinergic effect
         effects due to excess        should be the endpoint?
         acetylcholine
                                       - Pupil size?
       - Competitive inhibitor
                                       - Secretions?
       - Control of symptoms
                                       - Heart rate?
         determines the dose by
         titration                     - Blood Pressure?

                                       - Measurement of
                                         peripheral vascular
                                         resistance?


19
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   Atr opine r equir ement                  Atr opiniz ation

                                                 Poor air ent r y int o lungs caused by   Clear lungs
     40
                                                 br onchospasm and br onchor r hoea

                                                 Excessive sweat ing                      Dr y axillae
     30
                                                 ( Hypot ension)                          Syst ol. BP >
                                                                                          80 mm Hg
     20
                                                 ( Br adycar dia)                         Hear t r at e >
                                                                                          80/ min
     10                                          ( Miosis)                                No miosis


     0
          0          5         10           15
              min aft er fir st atr opine
                        dose




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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



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
                           30
           Case fatality




                           20



                           10



                            0
                                  98


                                          99


                                                 00


                                                        01


                                                               02
                                19


                                        19


                                               20


                                                      20


                                                             20


25
The results of observational data on gastric emptying
(GE) in pesticide self-poisoning

                                  Case fatality
                             Anuradhapura Hospital
                               in and not in RCT
                        75
                               No GE (in trial)
                               GE (NIT)
        Case fatality




                        50



                        25



                         0
                             GCS <14              GCS <10



26
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


        RO                                    H 3C       O E                       O E
             P O         +       EOH                 P O                   H 3C    P O       + X-
     H 3C                                 RO
             X                                       X       + H+             RO       Inhibition



                                       H ON     R                    H2O               H2O




                        RO                               HO                           O E
                             P O        EOH +                  P O            H 3C    P O      + R+ + H+
     EOH +       H 3C                                H 3C
                             O                              RO                        O
                                 N
                                 R
             Reactivatio                      Spontaneous reactivation               Aging
             n


                                                                     Worek et al. Biochem Pharmacol. 2004



28
AChE-Status in a Patient with Parathion Poisoning

                                            obidoxime
                             800                                          200
     activity (mU/µmol Hb)




                                             reactivatability
                             600                                          150           inhibitory activity




                                                                      poison
                             400                                          100

                             200                                               50
                                             RBC-AChE in vivo

                               0                                               0
                                   0   25     50       75       100                 0   25       50      75    100
                                               hours                                               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          55 cents / gram



30
... 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

     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




37
Comparative efficacy of i.v. pralidoxime vs. NaHCO3 in
rats lethally poisoned with OP insecticide (A Wong, Brazil)



8000                                                7012.12
7000
6000
5000
4000                                                           2611.17
3000
2000                                462.17
                      309.43
1000        0
   0
         D.D.V.P.     Atropine     Atrop. +         Atrop. +   Atrop. +
p<0.001 D~B and D~C                Oxime            Bicarb.     NaCl
p<0.01 D~E

                        N = 10 rats in each group


38
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
         - 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

								
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