What is the lethal dose of pyridostigmine?

Lethal Dose of Pyridostigmine

The lethal dose of pyridostigmine is not precisely established in humans, but severe toxicity can occur at doses of 600-900 mg, with death possible due to respiratory failure from cholinergic crisis.

Mechanism of Toxicity

Pyridostigmine is a reversible acetylcholinesterase inhibitor that causes accumulation of acetylcholine at cholinergic synapses. At toxic doses, this leads to:

• Excessive muscarinic stimulation: increased secretions, GI effects, bradycardia
• Excessive nicotinic stimulation: muscle fasciculations followed by weakness/paralysis
• Respiratory failure: the primary cause of death in severe overdose

Clinical Manifestations of Toxicity

Symptoms typically develop within minutes of ingestion and may progress in severity based on dose:

• Mild to moderate toxicity (seen with 390-600 mg):

  • Abdominal cramps, diarrhea, nausea, vomiting
  • Hypersalivation, urinary incontinence
  • Muscle fasciculations, weakness
  • Blurred vision 1

• Severe toxicity (>600 mg):

  • Progressive muscle weakness affecting respiratory muscles
  • Respiratory failure
  • Cardiovascular collapse with bradycardia 2

Distinguishing Cholinergic Crisis from Myasthenic Crisis

This distinction is crucial in patients with myasthenia gravis, as management differs dramatically:

• Cholinergic crisis (pyridostigmine overdose):

  • Requires immediate withdrawal of pyridostigmine
  • Atropine administration
  • Supportive care

• Myasthenic crisis (disease exacerbation):

  • Requires increased anticholinesterase therapy 2

Management of Pyridostigmine Overdose

1. Immediate interventions:

   • Secure airway, breathing, circulation
   • Gastric emptying followed by activated charcoal 1

2. Antidotal therapy:

   • Atropine: 1-8 mg IV as needed to control muscarinic symptoms 1
   • For severe cases: atropine may need to be administered in larger doses (up to 50 mg over 24 hours has been reported for organophosphate poisoning) 3

3. Supportive care:

   • Mechanical ventilation if respiratory failure occurs
   • Monitoring of vital signs and cholinesterase activity
   • Benzodiazepines may be helpful for agitation or seizures 3

Special Considerations

• Pyridostigmine overdose is generally self-limited in healthy adults 1
• Clinical recovery typically occurs faster than the normalization of cholinesterase activity 1
• Central nervous system manifestations are minimal with pyridostigmine compared to other cholinesterase inhibitors like physostigmine, as pyridostigmine has limited blood-brain barrier penetration 4

Monitoring

• Serum cholinesterase inhibition is a reliable diagnostic tool in pyridostigmine poisoning 1
• However, there is no clear correlation between the extent of cholinesterase inhibition and the severity of cholinergic signs 1

Potential Complications

• Anticonvulsant-resistant seizures have been reported with pyridostigmine, particularly when combined with other substances like DEET 5
• Cardiac arrhythmias may occur in severe cases

Prevention

For patients taking therapeutic pyridostigmine (for myasthenia gravis or other indications), dosing should not exceed the recommended maximum of 600 mg daily, with careful monitoring for signs of cholinergic excess 3.