organophosphate poisoning _wiki.ppt

South Asian Clinical Toxicology Research Collaboration

OrganophosphateOrganophosphate PesticidePesticide

PoisoningPoisoningOrganophosphateOrganophosphate PesticidePesticide

PoisoningPoisoning

Bishan RajapakseMBChB Otago

Emergency Medicine Advanced Trainee, MPhil Student (ANU), South Asian Clinical Toxicology Research Collaboration

Sri Lanka

Bishan RajapakseMBChB Otago

Emergency Medicine Advanced Trainee, MPhil Student (ANU), South Asian Clinical Toxicology Research Collaboration

Sri Lanka


The Case….The Case…. Picture yourself in Anuradhapura hospital Sri

Lanka – ED/ Medical SHO Ward 6 , teaming with patients…. Charge Sister tells you there is a sick patient

– 36yo F– Taken 100mls of Dimethoate after a domestic

argument There’s nowhere to run, or hide…. So you see

the patient – what do you do?


Organophosphate Pesticide Organophosphate Pesticide PoisoningPoisoning


Organophosphate Poisoning in Sri LankaOrganophosphate Poisoning in Sri Lanka

Organophosphate pesticide (OP) poisoning kills 300,000 worldwide– In Sri Lanka these are

mostly impulsive deliberate self-poisoning in young people


Organophosphate Poisoning in Sri LankaOrganophosphate Poisoning in Sri Lanka Case Fatality rates

(CFR)– 10-20% for most– 50-70% for some OP’s

In west CFR– 0.3% from all poisons

Multifactorial– Toxicity of OP’s– Patient transport– Lack of resources– Training

Although less common OP Poisoning is still a problem in West– Occupational exposure– Threat of Chemical warfare


Poisoning at Anuradhapura Hospital in Poisoning at Anuradhapura Hospital in 20052005

Poison Admissions Death Case Fatality

Acid 2 0 0%

Carbamate 105 3 3%

Hydrocarbon 62 0 0%

Medicine 254 3 1%

Oleander 380 8 2%

OP 408 44 11%

Other Pest. 311 12 4%

Paraquat 59 21 35.50%

Unknown 128 7 5.50%

Un.pesticide 127 13 10%

TOTAL 1836 111 6%


Mechanism of OP’sMechanism of OP’s


Simplified Acute OP ToxicitySimplified Acute OP Toxicity Inactivation of acetylcholinesterase enzyme

Organophosphate


Pharmacology of Cholinomimetics Pharmacology of Cholinomimetics according to Katzungaccording to Katzung

StructureSimple Alcohols eg edrophoniumCarbamates Eg Neostigmine and

Physostigmine (tertiary)

Organophosphates eg Parathion


Cholinomimetic Pharmacokinetics Pharmacodynamics

Simple AlcoholsEg edrophonium

Polar, not fat soluble Electrostatically bind to active site of AChE

(short lived 2-10mins)

Carbamates Tertiary – well absorbed, fat soluble Eg physostigmine

Quaternary- polar, negligible CNS distribution

2 step hydrolysis of to form Carbamoylated enzyme-inhibitor complex (30mins to 6 hours)

- Reversible inhibitors

Organophosphates Variable over 50,000 varieties

Most fat soluble- thus well absorbed and dangerous to humans

(Echothiopate is one of the water soluble varieties) Thiophosphates - need conversion to Oxon form to work

Malathion are metabolised to inactive forms in birds and mammals but not fish

Binding and hydrolysis to form Phosphorylated enzyme-inhibitor complex

Covalent phosphorus-enzyme hydrolyses slowly (hundreds of hours sometimes)-Irreversible inhibitors --May undergo Aging (different rates for different OPs) with no oxime regeneration thereafter


+ Death

Clinical Syndrome Acute Cholinergic:

– Central– Peripheral Muscarinic– Peripheral Nicotinic

Intermediate Syndrome OPIDN: Delayed peripheral neuropathy Neurocognitive dysfunction

Clinical SyndromeClinical Syndrome

Respiratory failure

Respiratory failure}}


Cholinergic EffectsCholinergic Effects

D iarrhoea U rination M iosis B radycardia, Bronchorrhoea, Bronchospasm E mesis L acrimation S alivation


Nicotinic EffectsNicotinic Effects Respiratory difficulty

– respiratory arrest– diaphragmatic weakness

Muscle Weakness– fasiculations– clonus– tremor

Stimulation of sympathetic nervous system– Mydriasis, hypertension, tachycardia– re-entrant dysrhythmias

– cardiorespiratory arrest


CNS effectsCNS effects Malaise Memory loss Confusion Disorientation Delirium Seizures Respiratory centre depression or dysfunction Coma


Intermediate SyndromeIntermediate Syndrome Delayed Respiratory Failure

– Proximal muscle weakness and cranial nerve lesions

– Typically 1-4 days after cholinergic crisis has resolved Prolonged Effects on Nicotinic receptors Primary motor end plate degeneration Clinical importance

– Delayed respiratory failure leads to death if not aware of it or prepared for it

Wadia et. al 1974 :Type II Paralysis, Senanayake and Karalliedde 1987


Chronic EffectsChronic Effects Organophosphate induced delayed

neuropathy (OPIDN) 1-3weeks Peripheral neuropathy Axonopathy due to Neuropathy Target Esterases

(NTE)

Chronic organophosphate induced neuropsychiatric disorder (COPIND)


ManagementManagementThe priorities in management are to:

Resuscitation Atropinisation of symptomatic patients

Decontamination Other Treatments - Oximes


AntidotesAntidotes Atropine Oximes

– Expensive Does treatment affect outcome

– Intermediate Syndrome?

– OPIDN?

? Dose ? Duration ? Effectiveness


Does the patient need Does the patient need atropine?atropine?

How much and for how long


Scheme of atropinization Scheme of atropinization (endpoints to be reached)(endpoints to be reached)

Eddleston M, Buckley NA, Mohamed F, Senarathna L, Hittarage A, Dissanayake W, Azhar S, Sheriff MHR, Dawson AH. Speed of initial atropinisation in significant organophosphorus pesticide poisoning - a comparison of recommended regimens. Journal of Toxicology – Clinical Toxicology 2004;6:865-875.

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


AtropineAtropine 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


What if you give too much Atropine ?What if you give too much Atropine ? Anticholinergic Syndrome:

– Hot as hell

– Blind as a bat

– Red as a beet

– Dry as a bone

– Mad as a hatter

A sensitive indicator for ingestion, but poor predictor for toxicity.

Full syndrome is rare


Gastrointestinal DecontaminationGastrointestinal Decontamination

?


Our Decision should depend Our Decision should depend on a risk/benefit analysison a risk/benefit analysis

Nothing Emesis Gastric Lavage Activated Charcoal Whole bowel irrigation


Risk of InterventionRisk of Intervention Aspiration

– Impaired GCS + Unprotected Airway Emesis, Lavage, Charcoal (worse with

cathartics) Trauma

– Oesphageal Injury Emesis, Lavage, Charcoal

Electrolyte Abnormalities Forced Emesis, Cathartics

Cardiac Arrest– Toxin induced bradycardia + Vagal Tone

Induced emesis, Lavage Cost


Summary of Experimental EvidenceSummary of Experimental Evidence Ideal settings

Little benefit in outcomes after 1 hour

Activated Charcoal is equivalent or better than emesis or lavage

Position statement: single-dose activated charcoal. J Toxicol Clin Toxicol 1997;35:721-41.

Position statement and practice guidelines on the use of multi-dose activated charcoal in the treatment of acute poisoning. J Toxicol Clin Toxicol 1999;37:731-51.


OximesOximes Ineffective in some situations

– Ageing– Variation between organophosphates

Effective protocols not established– Variation in use

Zero – 24 grams a day Expensive

USA $30-600 / gram India $6- 9 / gram Sri Lanka 55 cents / gram

Unlikely to address Non-ACh effects


Alternate sites for antidotesAlternate sites for antidotes

• Protect AChE• Supply AChE• Reduce ACh • Protect ACh

Receptor• Reduce OP Load• Multiple

Mechanisms


Other Treatments under Other Treatments under investigationinvestigation

Magnesium Reduces acetylcholine release Blockage pre-synaptic calcium channels Limited human studies

Clonidine Decrease the presynaptic synthesis and release of acetylcholine. Central nervous system > peripheral cholinergic synapses

Diazepam Diazepam reduces respiratory failure (rats) and cognitive

deficit (primates) Postulate “uncoordinated stimulation of the respiratory centres

decreases phrenic nerve output”.


The Case….The Case…. Picture yourself in Anuradhapura hospital Sri

Lanka – ED/ Medical SHO Ward 6 , teaming with patients…. Charge Sister tells you there is a sick patient

– 36yo F– Taken 100mls of Dimethoate after a domestic

argument There’s nowhere to run, or hide…. So you see

the patient – what do you do?


SummarySummary OP’s are Indirect Cholinomimetic

– Block AChE, prolonged duration of ACh in synapse

Effects– Muscarinic, Nicotinic, CNS– Respiratory failure and Death result from this

Treatment– ABC’s, Atropine, Decontaminate, Oximes

Important also in West

organophosphate poisoning _wiki.ppt

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