Organophosphate Poisoning

Created on Mon, 12/07/2015 - 13:32
Last updated on Sun, 12/20/2015 - 06:45

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Question 18.1 from the second paper of 2013 asked for six features of organophosphate poisoning. Additionally, a brief mention was made of cholinesterase mixing studies, for whatever reason. Organophosphate poisoning has also appeared during one of the recent vivas (Viva 5 from the second paper of 2015). Apart from the LITFL toxicology page on this topic (which is of course excellent and is everything you might need) the next best resource is an article by Walker and Nidiry from 2002.

Pharmacology of cholinesterase inhibitors

These are indirect cholinergic agents, drugs which inhibit acetylcholinesterase. They act as “amplifiers” of endogenous acetylcholine. They come in 3 distinct flavours: simple alcohols, carbamates and organophosphates. I am not going to go into chemical warfare agents here, but sarin gas is a notable member of this group of agents, and needs to be known about (though perhaps best left unmentioned during the viva station).

  • Simple alcohols eg. edrophonium
    • Bind reversibly to acetylcholinesterase
  • Carbamates eg neostigmine, pyridostigmine, physostigmine
    • Poorly absorbed
    • Most don’t get into the CNS- not lipid soluble enough (except physostigmine - it is very well absorbed, even through the skin)
    • These drugs carbamoylate acetylcholinesterase. This sounds unpleasant and takes up to 6 hours to reverse itself. The oint it, this is also reversible,
  • Organophosphates eg. Echothiopate, parathion
    • Very well absorbed, hence highly effective insecticides
    • Parathion in particular is poorly detoxified in vertebrates, and so is not available to every Joe Farmer
    • They phosphorylate the active site of the enzyme
    • This may take hundreds of hours to reverse
    • The bond becomes stronger with age!
    • Pralidoxime can be used to reverse the acetycholinesterase blockade if the bond hasn’t “aged”

Clinical features of acetylcholinesterase inhibitor toxicity

Cholinergic toxidromes can be remembered as SLUDGEM or DUMBBELS. I thank Yun from canberra who pointed out that DUMBBELS is the mnemonic for the muscarinic features, and the nicotinic features end up as the unpronounceable FTWRBHACS, which is resistant to mnemonification as it tends to break anagram engines.

Observe:

Muscarinic features Nicotinic features
  • Diarrhoea
  • Urination
  • Miosis
  • Bronchospasm
  • Bronchorrhoea
  • Emesis
  • Lachrymation
  • Salivation
  • Fasciculations
  • Tremor
  • Weakness
  • Respiratory muscle weakness
  • Bradycardia (tachycardia may be present)
  • Hypotension
  • Agitation
  • Coma
  • Seizures

The muscarinic effects are usually the first. CNS effects vary from alertness at low doses to seizures and coma at high doses. 

At low doses, anticholinesterase drugs cause a predominantly vagal response in the heart, with bradycardia and decreased cardiac output. There is usually not much change in blood pressure. At the neuromuscular junction, at low concentrations, these drugs prolong and intensify muscle contractions, which is good for people with myasthenia gravis.

As toxicity worsens, muscarinic secretory effects gain clinical dominance. Bronchorrhoea becomes so severe that it may resemble pulmonary oedema. Ganglionic stimulation overrides the vagotonic effect and tachycardia develops. Miosis is replaced by mydriasis. Excessive ganglionic stimuation leads to all manner of sympathetic-looking features, including hyperglycaemia, ketosis and lactic acidosis.

Higher concentrations will ultimately cause a depolarizing neuromuscular blockade. Sux-like fasciculations give way to flaccid paralysis. Many weeks down the track, peripheral neuropathies may develop, with distal muscle weakness and pain.

Management of organophosphate toxicity

Decontamination

  • Activated charcoal should be given if the OPs have been ingested - but usually it has no role to play, as most of the victims have either inhaled the drug or absorbed it through their skin.
  • Remove all clothing: it is probably contaminated.
  • Wash skin with water and soap to remove the remaining contaminant
  • Gastric lavage is indicated - the pesticides are usually in liquid form, and well susceptible to nasogastric drainage.

Enhanced elimination

  • Little can be done to enhance the elimination - these agents are usually fairly tenacious, with massive volumes of distribution. The exceptions are the carbamate molecules used in routine treatment of myasthenia gravis.

Specific antidotes

  • Atropine: massive doses will be required, well in excess of the usual 3mg limit. According to Goldfranks' manual, upwards of 1000mg of atropine may be required, and doses in excess of 11g have been reported in the literature. The usual trick is to keep doubling  the dose until a desired effect is achieved. In the words of the authors, " the end point is drying of pulmonary secretions with little regard for pupils or heart rate". If nicotinic features have developed, atropine therapy may be ineffective (an antimuscarinic drug can only defeat muscarinic effects).
  • Pralidoxime: needs to be given at the earliest opportunity, because the bond between the OP and the enzyme will 'mature" and become irreversible. The initial dose is 2g over 15 minutes, and it should be repeated every 6 hours until the patient has been asymptomatic for 24 hours. The positively charged quaternary nitrogen of pralidoxime is attracted to the negatively charged anionic site on the phosphorylated cholinesterase enzyme. There, pralidoxime can compete with cholinesterase for the phosphate moiety. If pralidoxime wins, it grabs the phosphate and the cholinesterase enzyme is released from the bond. In this fashion, pralidoxime is a cholinesterase-reactivating agent. Other "oximes" exist, most interestingly the Hagedorn oximes which have excellent efficacy in the treatment of neurotoxic  chemical warfare agents.

Supportive management

  • Intubation: lets face it, you're not going to get away without that. It goes without saying that suxamethonium and mivacurium should be avoided, because they are also metabolised by acetylcholinesterase.
  • Mechanical ventilation: this is one of those situations where you might prone-ventilate the patient purely because of massive secretory load, to improve postural drainage.
  • Circulatory support with vasopressors or inotropes may be required, as bradycardia and hypotension may be dominant features
  • Sedation with benzodiazepines is appropriate, because after that much atropine the patient will be delirious for an extremely long time, and short-acting agents would be a waste of time.

Cholinesterase mixing studies

  • In the mixing test, the patients serum and some random reference serum are both tested for plasma cholinesterase, and then a 50-50 mixture of the two is tested.
  • If there is enough pralidoxime being given, there will be little free organophosphate in the patient's sample, and the mixed sample will have a plasma cholinesterase level which is exactly between the patients sample and the reference sample.
  • If there is still free organophosphate present, then it will disable the plasma cholinesterase in the reference sample, and the cholinesterase level of the mixed sample will be surprisingly low.

 

References

Brian Kloss from LITFL has a superb cartoon to illustrate the horrors of the cholinergic toxidrome.

Sungur, Murat, and Muhammed Güven. "Intensive care management of organophosphate insecticide poisoning." Critical care 5.4 (2001): 211.

Kamanyire, R., and L. Karalliedde. "Organophosphate toxicity and occupational exposure." Occupational Medicine 54.2 (2004): 69-75.

Jr, Bailus Walker, and Joseph Nidiry. "Current concepts: organophosphate toxicity." Inhalation toxicology 14.9 (2002): 975-990.

de Jong, Leo PA, and Gre Z. Wolring. "Stereospecific reactivation by some Hagedorn-oximes of acetylcholinesterases from various species including man, inhibited by soman." Biochemical pharmacology 33.7 (1984): 1119-1125.