Question 8(p.2)

Describe the pharmacological basis of the management of organophosphate poisoning.

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College Answer

Organophosphates (OGP) bind irreversibly to acetyl cholinesterase. They produce a
cholinergic crisis and muscle paralysis due to excess Acetyl choline (ACh) at all muscarinic
and nicotinic receptors.
Candidates were required to discuss the pharmacology relevant to treating OGP poisoning,
including active decontamination/staff protection due to high lipid solubility, use of
antimuscarinics with central and peripheral action to treat cholinergic symptoms, supportive
therapy for muscle weakness (there is no antinicotinic agent available which does not
exacerbate muscle weakness), and finally the use of the cholinesterase regenerator, Pralidoxime, which may prevent the OGP-AChE complex ageing and becoming an irreversible bond if given in a timely fashion.
Good answers included a discussion of the mechanism of action of the therapeutic agents, the
time course of therapy, the large doses/infusions of atropine required and the titration of
therapy to reversal of muscarinic effects. Long lists of signs and symptoms were not required
to pass this question.
Syllabus H2b2c
Reference: Rang Dale Ritter 6th edition p 164-166
Katzung 10th edition p 116-117, 968.

Discussion

Toxicology has moved into the second part exam, but it never hurts to grapple with this early. Still, what is "pharmacological basis"? A clearer question (judging by what the answer they wanted looked like) should have been "Outline your management of a patient with organophosphate toxicity". As such:

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. 

Specific antidotes

  • Atropine
    • massive doses will be required,
    • doses in excess of 11g have been reported in the literature.
    • keep doubling  the dose until a desired effect is achieved.
    • the end point is drying of pulmonary secretions with little regard for pupils or heart rate
  • 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.
  • 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.

Supportive management

  • Intubation and mechanical ventilation
  • Prone position 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

References

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.