acetylcholinesterase inhibitor poisoning / organophosphate pesticides

see also:

• acetylcholinesterase inhibitors
• nerve agents / nerve gases / CBR weapons
• pharmacology main index
• toxicology
• parasympathetics

• Both organophosphate & carbamate insecticides are acetylcholinesterase inhibitors which are readily absorbed through intact skin or mucosa as well as from the GIT.
• Organophosphate inhibition is irreversible lasting months whereas clinical effects of carbamates last little more than 24hrs.
• Carbamates poorly pass BBB & thus have less CNS effects cf organophosphates.
• Inhibition of acetylcholinesterase leads to rapid accumulation of acetylcholine at the terminal endings of all postganglionic nerves, at both parasympathetic & sympathetic ganglia & myoneural junctions.
• In addition, organophosphate poisoning may cause a delayed neurotoxicity - Wallerian degeneration of mainly the large myelinated fibers resulting in a peripheral neuropathy.

• Classically, symptoms develop over a few hours (less if massive exposures or up to 2days if lipophilic) and present as the “SLUDGE” syndrome:
  • Salivation, Lacrimation, Urination, Diarrhoea, GIT effects, Everything else;
• Patients classically die from inability to aerate whilst drowning in their own secretions.
• The route of exposure usually determines the system effected first: inhalation: pulmonary; ingested: GIT;
• CNS effects are usually late, indicating a more severe ingestion.

• Stimulation of muscarinic parasymp. receptors:
  • see parasympathetics
  • miosis, bronchoconstriction, wheezing, SOB, nausea, vomiting, diarrhoea, tenesmus, fecal incontinence, urinary frequency & incontinence, excessive lacrimation, salivation, broncorrhoea, sweating, bradycardia, hypotension, ventricular tachycardia;
• Stimulation of nicotinic motor & sympathetic receptors:
  • tachycardia, palor, hypertension, hyperglycaemia, muscle twitching/fasciculations, weakness
• CNS effects if penetrate BBB:
  • emotional lability, restlessness, tremors, headaches, withdrawal & depression, drowsiness, lethargy
  • If highly toxic exposure, pts can quickly (min-hrs) progress to:
    • ataxia, generalised weakness, coma, convulsions, resp. depression, CVS depression
  • In children CNS effects usually predominated by lethargy or coma/stupor;
• The predominant symptoms/signs may not be diagnostically useful in young children as:
  • they tend to cry anyway
  • they are usually incontinent of urine & faeces under age 2-3yrs when most ingestions occur
• Classification of severity:
  • may be done by using % of baseline RBC cholinesterase still available:
    • mild - 20 to 50%
    • moderate - 10 to 20%
    • severe - < 10%
  • NB. blood samples should be refrigerated & analysed within 24-48hrs;

• usually occur within 2wks exposure & last several months:
• polyneuropathies - paraesthesias, weakness, muscle cramps, altered gait, drowsiness, emotional lability, depression, irritability.
• NO long term effects described in children.

• Staff should follow their local biohazard procedures and at least be gowned & double-gloved, & should avoid inhaling vapors of vomitus, etc.
• ABC's, Oxygen if needed
• Decontaminate skin, eyes to prevent ongoing absorption:
  • remove clothes
  • thoroughly cleanse skin - at least 2 separate water & detergent washes will remove up to 94% of residual organoP, even if done up to 6hrs after exposure;
  • consider giving activated charcoal with sorbitol if recent ingestion & no C/I
• contact a clinical toxicologist or poisons information centre
• All pts with suspected exposure, insert IV line & commence atropinisation to minimise bronchorrhoea:
  • 1.2mg (0.05mg/kg up to 1.2mg) atropine by slow injection whilst monitoring ECG & obs
    • Double the dose every 5 minutes until the target end points below are reached.
    • In some cases, cumulative loading doses up to 100 mg may be required.
    • target end points:
      • clear chest with no wheeze on auscultation
      • HR > 80/min
      • systolic BP > 80mmHg
  • 0.6mg (0.02mg/kg up to 0.6mg) IV atropine should preferably be given BEFORE intubation (unless patient is in cardiac arrest) as this will block the vagal response to intubation which can precipitate profound bradycardia
  • further maintenance doses of atropine should be given if signs of atropine excess appear to be reversing, atropinisation should be continued for:
    • organoP - at least 24hrs with tapering of dose after 12hrs if clinically OK
    • lipophilic organoP - longer duration Rx
    • carbamates - shorter duration of Rx
  • Atropine will not affect nicotinic (skeletal muscle & sympathetic ganglia) receptors.
    • in patients have neuromuscular paralysis, ventilation is usually required for as long as 2 to 3 weeks
    • Adverse effects of atropine include:
      • fever, muscle fasciculations, delirium, dry eyes, adynamic bowel, unresponsive pupils
• Take bloods for RBC cholinesterase activity;
• Mx of hypotension
  • first-line treatment is intravenous fluid resuscitation.
  • if hypotension persists, start inotropic support and seek advice from a clinical toxicologist.
• Mx of seizures
  • Seizures are uncommon but may indicate severe poisoning, inadequate atropinisation, or hypoxia.
  • if persistent or recurrent, treat with an intravenous benzodiazepine and atropine.
• The role of pralidoxime:
  • Pralidoxime is a cholinesterase reactivator at the NM junction, and is effective for some of the nicotine effects & thus helpful for re-establishing resp. muscle & diaphragm movement, but does not cross BBB & thus CNS dysfunction is not helped.
  • Pralidoxime use for organophosphate poisoning is controversial and routine use is not recommended.
  • There is evidence that pralidoxime may increase the toxicity of carbamates & thus should only be used in organoP poisonings, after adequate atropinisation & only if resp. depression or unresponsive cardiac arrhythmias, although some feel it is appropriate to use if more than 2 doses of atropine have been needed in organoP poisonings.
  • Dose of pralidoxime iodide if indicated:
    • 15mg/kg IV up to 1g over 15-30min in 100mL 0.9% saline
    • followed by 10 mg/kg/hour up to 250 mg/hour IV infusion whilst cholinergic signs persist or at review and decision at 12-24hrs. Lower maintenance dose if renal impairment.
    • NB. Pralidoxime iodide is the only pralidoxime salt available in Australia; if using pralidoxime chloride, the dose equivalence is 1 g pralidoxime iodide = 0.65 g pralidoxime chloride.
  • Administration should commence within 36hrs of exposure otherwise it may not work due to a process called “aging” of the organoP-enzyme complex.
  • Adverse effects of pralidoxime:
    • dizziness, headache, nausea, blurred vision, muscle weakness.
• Patient Disposition:
  • Admit for observation (for 36-72hrs?) if symptomatic or if suspected exposure in a child & Mx
  • Possibly home if asymptomatic after several hours observation.

• shorter effect - usually only lasting 24hrs (cf months)
• do not pass BBB & thus have less CNS effects
• C/I to use pralidoxime as evidence that this makes carbamate toxicity worse!

aldicarb oxamyl carbofuran methomyl (Lannate) formetanate

aminocarb dimetilan dimetan dioxacarb methiocarb propoxur (Baygon) bendiocarb

pirimicarb bufencarb MTMC MPMC isoprocarb carbaryl

azinphos-methyl bomyl carbophenothion chlorfenvinphos chlormephos coumaphos cyanofenphos dialifor dicrotophos dimeton+ disulfoton+ EPN ethyl parathion famphur fenamiphos fenophosphon fonofos fensulfothion fonofos isofenphos methamindophos methidathion methyl parathion mevinphos monocrotophos phorate phosfolan phosphamidon protothoate schradan sulfotepp terbufos tetraethyl pyrophosphate (TEEP) triamiphos Moderately toxic organophosphates (LD50 > 50mg/kg rats): bromophos-ethyl chlorpyrifos crotoxyphos cyanophos cythioate DEF demeton-methyl+ diazinon dichlofenthion dichlorvos dimethoate dioxathion EPBP ethion ethoprop fenitrothion fenthion formothion heptenephos osoxathion leptophos naled phencapton phenthoate phosalone phosmet profenofos propetamphos pyrazophos pyridaphenthion quinalphos sulprofos triazophos trichlorfon thiometon

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