Physostiigmine

• Introduction
  • Naturally-occuring plant-derived alkaloid; is a carbamate that reversibly inhibits cholinesterases in the PNS and CNS
  • Is a tertiary amine à allows CNS penetration (where the quaternary amine structure of neostigmine and pyridostigmine limits CNS penetration)
  • Used to treat anticholinergic effects of numerous medications and toxins incluiding, TCAs and phenothiazines
  • Single study found to address use as a diagnostic tool in suspected anticholinergic syndrome

• Mechanism of action:
  • Reversibly binds to acetylcholinesterase
    • Is metabolized by acetylcholinesterase. While the time to hydrolysis of acetylcholine is 150msec, the half-life to hydrolysis in physostigmine is 15-30 minutes. Result is active acetylcholine in the synapse for a prolonged duration

• Absorption: Poor oral bioavailability - 5-12%

 

• Volume of distribution: humans 0.664L/kg; distribution half-life of 2.3 minutes

 

• Onset of action: Peak serum levels and initial effect seen within 2 minutes of IV administration; peak effect within 15 minutes (early studies suggested quicker peak effect).

 

• Metabolism:
  • Though the half-life measured in the serum is 16-23 minutes, the observed half-life of plasma cholinesterase inhibition is 83-100 minutes with full recovery seen within 3 hours of cessation of infusion
  • Suspected that 90% of physostigmine is metabolized by the liver within 2 minutes. The rest is metabolized locally by cholinesterase. Elimination half-life 16-23 minutes

 

• Indications:
  • Peripheral or central anticholinergic manifestations
    • Peripheral: dry mucosa, dry skin, flushed face, mydriasis, hyperthermia, decreased bowel sounds, urinary retention, tachycardia
    • Central: agitation, delirium, hallucinations, seizures, coma

 

• Dosing: 1-2mg (0.02mg/kg, max 0.5mg in children) infused over 5-10 minutes, can redose in ~15 minutes if no effect, redose in ~1 hour if initial effect that wanes
  • Comes in 2mL, 1mg/mL ampules
  • Case reports of infusion after initial doses lost effect (below)

 

• Major interactions
  • Suspected interactions like RAD, intestinal/bladder obstruction
  • Potentiation of paralysis with succinylcholine administration, potential inhibition/reversal of paralysis with non-depolarizing paralytic administration
  • Physostigmine salicylate injection contains sodium metabisulfite; can cause anaphylactoid reactions in patients with sulfa allergies

 

• Management
  • Before use, want to obtain ECG for potential QRS or QTc changes, (QRS < 100msec, PR < 200msec)
  • Continue cardiac monitoring with pulse oximetry

 

• Use as an antidote
  • Once was commonly used as an antidote in a wide range of anticholinergic poisonings
  • However, use declined after case reports were published linking physostigmine use in TCA overdose to asystole (patients in cited literature had prolonged QRS intervals)
  • More recent reviews have found little evidence that TCA ingestion or ECG changes should be used as a contraindication to physostigmine use for anticholinergic syndromes
    • Cited issues seem to be speed of physostigmine infusion
  • Many papers that support use as a bolus (dosing as above)
  • Shown to be superior to benzodiazepines in controlling anticholinergic agitation and delirium
    • Improved efficacy, decreased rates of intubation
  • Has been given as a continuous infusion for persistent anticholinergic symptoms in overdose

 

• Clinical toxicity
  • Cholinergic crisis:  sweating, salivation, vomiting, diarrhea, urinary incontinence, bronchorrhea, bradycardia, hypotension, weakness, paralysis
  • Potential to cause seizure
  • Recommended to have atropine at the bedside of patients receiving physostigmine in the instance of overshooting the therapeutic target (especially with infusions)

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
References
Arens, AM et al. Safety and effectiveness of physostigmine: a 10-year retrospective review. Clin Toxicol (Phila). 2017 Jul 13:1-7.
Beaver KM, Gavin TJ. Treatment of acute anticholinergic poisoning with physostigmine. Am J Emerg Med. 1998 Sep; 16(5):505-7.
Buck ML and Reed MD. Use of nondepolarizing neuromuscular blocking agents in mechanically ventilated patients. J Clin Pharm. 1991 Jan;10(1):32-48.
Burns MJ, Linden CH, Graudins A, Brown RM, Fletcher KE. A comparison of physostigmine and benzodiazepines for the treatment of anticholinergic poisoning. Ann Emerg Med. 2000 Apr; 35(4):374-81.
Dawson, Andrew H., and Nicholas A. Buckley. Pharmacological Management of Anticholinergic Delirium ‐ Theory, Evidence and Practice. British Journal of Clinical Pharmacology 81.3 (2016): 516–524. PMC. Web. 18 Sept. 2017.
Hail SL, Obafemi A, Kleinschmidt KC. Successful management of olanzapine-induced anticholinergic agitation and delirium with a continuous intravenous infusion of physostigmine in a pediatric patient. Clin Toxicol (Phila). 2013 Mar; 51(3):162-6.Knapp  S, Wardlow  ML, Albert  K  et al.: Correlation between plasma physostigmine concentrations and percentage of acetylcholinesterase inhibition over time after controlled release of physostigmine in volunteer subjects. Drug Metab Dispos.1991;19:400–404.Pentel, P and Peterson, CD. Asystole complicating physostigmine treatment of tricyclic antidepressant overdose. Ann Emerg Med. 1980 Nov;9(11):588-90.
Rosenbaum, Christopher, and Steven B. Bird. “Timing and Frequency of Physostigmine Redosing for Antimuscarinic Toxicity.” Journal of Medical Toxicology 6.4 (2010): 386–392. PMC. Web. 18 Sept. 2017.
Phillips, Michelle A. et al. Use of a Physostigmine Continuous Infusion for the Treatment of Severe and Recurrent Antimuscarinic Toxicity in a Mixed Drug Overdose. Journal of Medical Toxicology 10.2 (2014): 205–209. PMC. Web. 18 Sept. 2017.
Schneir AB, Offerman SR, Ly BT, Davis JM, Baldwin RT, Williams SR, Clark RF. Complications of diagnostic physostigmine administration to emergency department patients. Ann Emerg Med 2003; 42: 14–9.
Suchard, JR. Assessing physostigmine's contraindication in cyclic antidepressant ingestions. J Emerg Med. 2003 Aug;25(2):185-91.
Triggle, DJ. Mitchell, JM, and Filler, R. The pharmacology or physostigmine. CNS Drug Reviews, Vol. 4, No. 2, 1998. 87-136.
Watkins JW, Schwarz ES, Arroyo-Plasencia AM, Mullins ME. The Use of Physostigmine by Toxicologists in Anticholinergic Toxicity. J Med Toxicol. 2015 Jun; 11(2):179-84.