All Pharmacy Pearls

Introduction

    abundant in prescription and over the counter (OTCs)

  • 2. Their ease of access to anticholinergic drugs and lack of

    • concern by most patients for serious adverse effects

    make them potentially dangerous drugs

  • 3. Anticholinergic toxicity can lead to a complex toxidrome

    • characterized in the CNS by hallucinations, delirium,

    agitation and seizures

  • 4. Non-CNS effects can include dry mouth, mydriasis,

    • blurred vision, decreased/absent bowel sounds, urinary

    retention, dry and flushed skin, tachycardia, and

    hyperthermia.

  • 5. The earliest documented use of physostigmine to reverse

    • anticholinergic delirium was in 1864 by Kleinwachter who

    treated prisoners who had mistakenly consumed

    atropine

  • 6. Case reports from the 1980-90s showed an association

    • between physostigmine use and worsened patient

    outcomes, which has led to a drastic decline in its use for

    anticholinergic toxicity

  • 7. These case reports involved physostigmine administration

    • in the setting of TCA toxicity with prolonged QRS have

    been the most common situation which displayed

Pharmacology

PropertyPhysostigmine
DoseIV: 0.5 to 2 mg
Repeat every 5 min PRN to reverse agitation
2 mg cumulative MAX
AdministrationSlow IV Push ~3–5 min
FormulationIV: 2 mg/2 mL vials
PK/PDOnset ~1 min
Duration 30–60 mins
Adverse EffectBradycardia
Bronchospasm
Bronchorrhea
Diaphoresis
Muscle fasciculation
WarningsConvulsions may occur with overly rapid IV administration
ContraindicationQRS > 100 msec
TCA toxicity

Evidence

Author, YearDesign / Sample SizeOffending Agents Causing ToxicityOutcome
Boley SP, 2018Prospective observational analysis
n=154		Antihistamines (68%), analgesics (19%), and antipsychotics (19%)Delirium control in 79% of patients who received physostigmine versus 36% of those who did not (OR 6.6)

No difference in adverse events with physostigmine vs standard of care
Arens, 2018Retrospective cohort study
n=191		Anticholinergic plant (35.1%), Diphenhydramine (29.3%), other antihistamines (7.3%), TCAs (1.6%), other agents (26.7%)Patients exposed to non-diphenhydramine antihistamines, antipsychotics, and tricyclic antidepressants had 100% response to physostigmine

74.3% treated with physostigmine alone

One dose was effective in reversing or improving anticholinergic delirium in a majority (73.8%) of the patients
Rosenbaum, 2010Retrospective study
n=45		Undefined anticholinergic agents31% received repeat dosing of physostigmine

45% of patients were d/c from ED

Patients are not likely to require repeat physostigmine dosing more than 6.5 h from their first dose
Weizberg, 2006Case series
n=2		Olanzapine overdose1.5–2 mg of physostigmine led to regaining full consciousness
Burns, 2000Retrospective study
n=52		Undefined anticholinergic agentsPhysostigmine controlled agitation and reversed delirium in 96% and 87% of patients vs benzodiazepines controlled agitation in 24% and were ineffective in reversing delirium

Physostigmine had lower incidence of complications and shorter time to recovery
Pentel, 1980Case series
n=2		TCA with prolonged QRS intervals (120 and 240 msec)Both patients developed bradycardia and asystole after receiving physostigmine

Conclusions

anticholinergic toxidrome. Minimal adverse effects have been reported as long as there is no report of TCA

ingestion and QRS < 100 msec. However, patient’s delirium will return once the physostigmine wears off, so repeat

dosing may be needed.

References

1.
Physostigime. Micromedex [Electronic version].Greenwood Village, CO: Truven Health Analytics. Retrieved September 6, 2018, from
http://www.micromedexsolutions.com/
2.
Boley SP, et al. Physostigmine is superior to non-antidote therapy in the management of antimuscarinic delirium: a prospective study
from a regional poison center. Clin Toxicol. 2018 Jun 29. Epub ahead of print. PMID 29956570
3.
Arens AM, et al. Safety and effectiveness of physostigmine: a 10-year retrospective review. Clin Toxicol (Phila). 2018 Feb;56(2):101-107.
4.
Rosenbaum C,et al. Timing and frequency of physostigmine redosing for antimuscarinic toxicity. J Med Toxicol. 2010 Dec;6(4):386-92
5.
Weizberg M, et al. Altered mental status from olanzapine overdose treated with physostigmine. Clin Toxicol (Phila). 2006;44(3):319-25.
6.
Burns MJ, et al. A comparison of physostigmine and benzodiazepines for the treatment of anticholinergic poisoning. Ann Emerg Med.
2000 Apr;35(4):374-81
7.
Pentel P, et al. Asystole complicating physostigmine treatment of tricyclic antidepressant overdose. Annals of emergency medicine.
1980;9:588-90.
Tags: 0.5 to 2 mg anticholinergic delirium QRS

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