Dr Martin Wilks, Syngenta Crop Protection AG, Basel, Switzerland 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

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

Organophosphate Carbamate O(S) II P - O - X O II R1 - NH - C - O - R2 R1,2 = alkyl or aryl groups X = wide range of branched or substituted groups R1 = methyl, aromatic or benzimidazol group R2 = aromatic or aliphatic group

Acetylcholinesterase and OP Organophosphate

Nicotinic, muscarinic and central syndrome

Respiratory failure Central Peripheral Muscarinic Peripheral Nicotinic Clinical Syndromes Acute Cholinergic: Central Peripheral Muscarinic Peripheral Nicotinic Intermediate Syndrome Delayed peripheral neuropathy Neurocognitive dysfunction Respiratory failure 8

Acute Cholinergic Syndrome

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

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

Relative human toxicity of pesticides in self-poisoning X symptomatic 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

Fenthion poisoning

Dimethoate poisoning

Complicates Assessment of the Evidence OPs are different Differing Toxicity Different Kinetics Different Clinical Syndromes Different Response to Antidotes ? Need Different Treatment Responses Complicates Assessment of the Evidence

Sequence of Medical Management Basic Supportive Care Does the patient need Atropine ? Poor air entry into the lungs due to bronchorrhoea and bronchospasm Bradycardia Excessive sweating Small pupils Hypotension. Decontamination ? Oximes? Adjunctive Treatment ?

Atropine – mechanism and endpoints Which cholinergic effect should be the endpoint? Pupil size? Secretions? Heart rate? Blood Pressure? Measurement of peripheral vascular resistance? Mechanism Blocks the muscarinic effects due to excess acetylcholine Competitive inhibitor Control of symptoms determines the dose by titration

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

Range of times it would take to give adequate doses of atropine (23mg and 75 mg) following the expert advice from each text

Scheme of atropinization (endpoints to be reached) 5 1 2 3 4 m i n a f t e r s o p d 8 6 A q u P y l g c b h E x v w ( H ) B M z C D S . > / N

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

Decontamination Don’t confuse creating mess with efficacy Decisions based on risk/benefit analysis

Gastric emptying – what happens if you stop?

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

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

Therapy with Oximes: Basics 3 P O + EOH P O H C P O + X - H C R O 3 3 X X + H + R O Inhibition H O N H O R H O 2 2 R O H O O E P O + EOH + P O H C P O + R + H + EOH + H C H C 3 3 3 O R O O N R Reactivation Spontaneous reactivation Aging Worek et al. Biochem Pharmacol. 2004

AChE-Status in a Patient with Parathion Poisoning obidoxime 200 inhibitory activity 150 poison 100 50 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

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

... 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

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

Magnesium Pajoumand A et al (2004) Hum Exp Toxicol 23(12):565-9 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

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?

Diazepam Synergistic response with anticholinergics Dickson EW et al Diazepam inhibits organophosphate-induced central respiratory depression. Acad.Emerg.Med. 2003;10(12):1303-

Organophosphates and pH Organophosphate Hydrolase is pH sensitive. Binding of pralidoxime is pH sensitive. Acetylcholinesterase Aging of OP-AChe complex and reactivation. Organophosphate In organophosphate poisoning it is known that the function of Organophosphate Hydrolase is pH sensitive. In addition, the binding of pralidoxime is pH sensitive. The function of acetylcholinesterase AChE , aging of OP-AChe complex and reactivation is also pH sensitive.

Comparative efficacy of i. v. pralidoxime vs Comparative efficacy of i.v. pralidoxime vs. NaHCO3 in rats lethally poisoned with OP insecticide (A Wong, Brazil) 5 Groups of 10 rats DDVP only (no treatment) 0/10 Atropine (17 mg/kg) alone 3/10 Atropine + pralidoxime (1 g/kg) 4/10 Atropine + NaHCO3 (3 meq/kg) 9/10 Atropine + NaCl 0.9% (1.9 ml/kg) 5/10

Comparative efficacy of i. v. pralidoxime vs 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 Bicarb. NaCl 309.43 462.17 7012.12 2611.17 1000 2000 3000 4000 5000 6000 7000 8000 p<0.001 D~B and D~C p<0.01 D~E N = 10 rats in each group

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

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

Andrew Dawson Michael Eddleston Horst Thiermann Special thanks to for helpful discussion, permission to use their slides, and many shared drinks