Physostigmine


Article Author:
Olyn Andrade


Article Editor:
Anoosh Zafar Gondal


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Mayank Singhal


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Nazia Sadiq
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Phillip Hynes


Updated:
7/31/2019 8:30:16 AM

Indications

Physostigmine is a tertiary amine, and a reversible cholinergic medication most commonly used in the management and treatment of antimuscarinic toxicity and glaucoma. Physostigmine originates from the Calabar bean, commonly found in the African tropics.[1][2] Although small in size, it's fatalness was first discovered by Sir Robert Christison in 1855. A few decades later, in 1863, Sir Thomas Richard Fraser, wrote his thesis on the medicinal uses of physostigmine. From 1863 to this day, there has been extensive research done on the uses of physostigmine, examining its use in the treatment of glaucoma to its use in the treatment of septic shock.[1][3]

Physostigmine salicylate has FDA approval for use in the treatment of glaucoma, as well as the treatment of anticholinergic toxicity. It is used to treat the central nervous system effects of anticholinergic toxicity due to its ability to cross the blood-brain-barrier.[4] The symptoms associated with anticholinergic toxicity are delirium, tachycardia, mydriasis, urinary retention, dry skin, and ileus. 

Concerning the treatment of glaucoma, physostigmine increases the levels of acetylcholine available for the ciliary muscle of the eye to contract. This increase results in increased aqueous humor flow and a decrease in intraocular pressure. Due to its increased side effects, medications with fewer side effects are preferable for the treatment of glaucoma.[1][5]

Recent studies have examined the use of physostigmine in systemic inflammation, sepsis, and nerve gas exposure. A randomized, double-blind placebo-controlled monocentric pilot trial performed between 2015 and 2017 with 20 enrolled patients looked at the effects of physostigmine in patients following intra-abdominal infections leading to septic shock. There was no statistical significance in the outcome between the two groups of placebo (0.9% sodium chloride) and physostigmine salicylate. Treatment with physostigmine salicylate was found to be feasible and safe. Future research looking at a large sample size is necessary to assess the effects of physostigmine on recovery from septic shock.[3] A study published in 2018 proposed using physostigmine loaded liposomes to protect against nerve gas exposure. Nerve gas commonly affects acetylcholinesterase by amplifying its action. Physostigmine can reversibly bind to acetylcholinesterase and block the effects of nerve gas. Liposomes were used in this study to prolong the half-life of physostigmine, which usually has a half-life of 23 minutes.[6][7] 

Mechanism of Action

Physostigmine functions as a cholinergic medication by increasing the amounts of acetylcholine present at cholinergic synapses in the central and peripheral nervous systems. This medication inhibits the actions of acetylcholinesterase and butyrylcholinesterase, enzymes that normally break down acetylcholine.[8] Through this mechanism, acetylcholine accumulates at synapse sites of muscarinic or nicotinic receptors, triggering action potentials. This action leads to the muscarinic receptor effects of decreased pupil size, increased aqueous humor production, increased salivation, increased gastrointestinal secretions, increased urination, and sweating.[4] Nicotinic effects are those affecting striated muscle or sympathetic ganglia. Symptoms consist of cramps, fasciculations, twitching, weakness, elevated blood pressure, and tachycardia. Central nervous system effects are ataxia, and convulsions eventually leading to coma.[5]

Administration

Administration of Physostigmine

For anticholinergic toxicity:

  • Adults - Intramuscular or Intravenous: Start initially at 0.5 mg to 2 mg, with a minimum delay of at least 10 to 30 minutes before dosing if symptoms persist and are severe, with the absence of cholinergic signs. Infuse at a rate of 1 mg/minute in adults.
  • Pediatric - Intramuscular or Intravenous: Start at 0.02 mg/kg, with a maximum dose of 0.5 mg/dose, 2 mg total; repeated every 5 to 10 minutes if symptoms persist and are severe, with the absence of cholinergic signs. Infuse at a rate no faster than 0.5 mg/minute in the pediatric population. 

For non-depolarizing neuromuscular blockade reversal:

  • Adults - Intramuscular or Intravenous: Start initially at 0.5 mg, with a minimum delay of at least 10 to 15 minutes before re-dosing, up to a maximum dose of 2 mg in the first hour.[6] Infuse at a rate no faster than 1mg/minute in adults. 
  • Pediatric - Intramuscular or Intravenous: Start initially at 0.01 mg/kg to 0.02 mg/kg in children, with a minimum delay of at least 10 to 15 minutes before re-dosing, up to a maximum dose of 2 mg in the 1st hour.[6] Infuse at a rate no faster than 0.5 mg/minute in the pediatric population.

Important note: When dosing with physostigmine, keep atropine available for any severe cholinergic symptoms. 

Adverse Effects

Significant adverse effects seen with the use of physostigmine are rarely reported and are most commonly related to overdose or seen in patients who have contraindications. 

Severe adverse effects:

  • Cholinergic crisis 
  • Bradycardia 
  • Hypotension
  • Seizures/hallucinations
  • Anaphylaxis - especially in those with salicylate/sulfite allergies
  • Respiratory depression 
  • Cardiac arrest 

Common reactions:

  • Nausea/vomiting 
  • Diarrhea 
  • Abdominal cramps 
  • Lacrimation 
  • Dyspnea
  • Miosis
  • Sweating 

In a literature review looking at 161 articles and a total patient population of 2299, adverse effects of physostigmine occurred in 415 patients. These adverse effects mainly consisted of hypersalivation in 206 patients and nausea and vomiting in 96 patients. Patients who had seizures consisted of 15. Symptomatic bradycardia occurred in eight patients, of which three patients had bradycardic-asystolic arrests. Ventricular fibrillation occurred in one patient, who had an underlying coronary artery disease.[4]

Contraindications

Contraindications for physostigmine use include the presence of:

  • Pulmonary disease-causing bronchoconstriction of the airways such as asthma
  • Gangrene
  • Diabetes
  • Cardiovascular disease
  • Gastrointestinal or urogenital tract obstruction
  • Angle-closure glaucoma
  • Coexisting medications with choline esters and depolarizing neuromuscular blockers or a salicylate/sulfite allergy

Caution is necessary when administering to patients with bradycardia, vagal tone increase, peptic ulcer disease, gastroesophageal reflux disease, hypotension, hyperthyroidism, and those with seizure disorders. 

Patients with QRS prolongation on EKG or those with a history of overdose with QRS prolonging medications should not receive physostigmine.[4]

Monitoring

Physostigmine administered via the intravenous route has rapid distribution and plasma elimination; distribution is 2.3 minutes while elimination half-life is 23 minutes.[6]

There are no recommended routine tests for the use of physostigmine. Monitoring of the effects of physostigmine can be done using an EKG and vital signs. 

The most significant side effect is a cholinergic crisis, which is avoidable by administering physostigmine at the dosage protocols while keeping contraindications and cautions in mind. 

Physostigmine is deemed pregnancy Category C. In a study looking at information collected between 2010 and 2012 by the Toxicology Investigators Consortium (ToxIC) Registry of the American College of Medical Toxicology, suggested that physostigmine was used in 4% of cases that involved pregnant women (N=103).[9]

Toxicity

The antidote for physostigmine toxicity is atropine.[10]

Enhancing Healthcare Team Outcomes

Managing physostigmine dosing requires multiple healthcare professionals from the physician to the pharmacist and the eventual team member who administers the drug, the nurse. It is of utmost importance that those involved in the care of patients who require physostigmine understand the mechanism of action, dosing protocols, and toxicity treatment. When toxicity occurs, the nurse may be the first to notice it and report to the healthcare team; it is up to the clinician to consult with the pharmacist to determine the proper dosing of atropine required to keep the patient stable and in no acute distress. Pharmacy and the ordering clinician are also responsible for medication reconciliation, to avoid drug-drug interactions. After stabilizing the patient, it is up to the healthcare professionals involved in the care, to collaboratively determine the reason behind toxicity. Protocols should be changed if necessary.

Because of the potential for cholinergic toxicity, physostigmine therapy requires an interprofessional team approach, including physicians, specialists, specialty-trained nurses, and pharmacists, all collaborating across disciplines to achieve optimal patient results. [Level V]


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Physostigmine - Questions

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A 16-year-old male presents to the emergency room with symptoms consistent of an overdose. When asked what he had been exposed to, he says he does not remember exactly but that he had picked up eye drops from a friend's house and ingested them in a suicide attempt. He has symptoms of tachycardia, flushing, delirium, and upon examination, mydriasis. What is the most appropriate medication given for this overdose?



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A 16-year-old patient comes into the local emergency department after smoking a type of weed with his friends. He complains of nausea, a dry mouth, blurry vision, twitching and feels like his heart is racing. What is the most appropriate treatment for his toxicity?



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A 25-year-old female patient comes to the emergency department complaining of hallucinations, blurred vision, a dry throat, and an inability to urinate. Upon examination, she has dilated pupils and slurred speech. She is diagnosed and managed with medication. Several hours later, her symptoms have changed. She now complains of vomiting, GI distress, excessive salivation. Which one of the following is a side effect of her initial treatment, if given in excess?



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What is the best treatment for myasthenia gravis?



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An elderly patient with a medical history significant for depression, Parkinson disease, schizophrenia, epilepsy, and lung cancer is admitted to the emergency department from a group home for severe agitation and delirium after suspected toxic encephalopathy. Collateral history from a resident of the home reveals empty bottles, including one of amitriptyline. The patient is known to take benzatropine and chlorpromazine as part of his home medications. An initial EKG shows a widened QRS interval of 125 milliseconds. The intern orders an antidote that is delivered intravenously after which the patient develops asystole following administration. Which of the following drugs is most likely to have precipitated this event in this patient?



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A 25-year-old woman comes into the emergency department. Upon examination, she is tachycardic, has decreased bowel sounds, and is unable to urinate. She informs the healthcare provider that she recently tried smoking a new weed. An antidote is promptly administered to this patient. What is this antidote targetting?



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A 17-year-old male patient comes in with symptoms of poisoning after smoking a certain weed found in the wild. The antidote is a drug in the same class of drugs used to treat myasthenia gravis. Which of the following is a side effect commonly seen with the administration of this drug?



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Physostigmine - References

References

Pinheiro GKLO,Araújo Filho I,Araújo Neto I,Rêgo ACM,Azevedo EP,Pinheiro FI,Lima Filho AAS, Nature as a source of drugs for ophthalmology. Arquivos brasileiros de oftalmologia. 2018 Sep-Oct;     [PubMed]
Proudfoot A, The early toxicology of physostigmine: a tale of beans, great men and egos. Toxicological reviews. 2006;     [PubMed]
Pinder N,Bruckner T,Lehmann M,Motsch J,Brenner T,Larmann J,Knebel P,Hoppe-Tichy T,Swoboda S,Weigand MA,Hofer S,Zimmermann JB, Effect of physostigmine on recovery from septic shock following intra-abdominal infection - Results from a randomized, double-blind, placebo-controlled, monocentric pilot trial (Anticholium® per Se). Journal of critical care. 2019 Apr 9;     [PubMed]
Bitzinger DI,Gruber M,Tümmler S,Malsy M,Seyfried T,Weber F,Redel A,Graf BM,Zausig YA, In Vivo Effects of Neostigmine and Physostigmine on Neutrophil Functions and Evaluation of Acetylcholinesterase and Butyrylcholinesterase as Inflammatory Markers during Experimental Sepsis in Rats. Mediators of inflammation. 2019;     [PubMed]
Arens AM,Kearney T, Adverse Effects of Physostigmine. Journal of medical toxicology : official journal of the American College of Medical Toxicology. 2019 Feb 11;     [PubMed]
Dawson AH,Buckley NA, Pharmacological management of anticholinergic delirium - theory, evidence and practice. British journal of clinical pharmacology. 2016 Mar;     [PubMed]
Park JH,Lee JY,Kim KT,Joe HE,Cho HJ,Shin YK,Kim DD, Physostigmine-loaded liposomes for extended prophylaxis against nerve agent poisoning. International journal of pharmaceutics. 2018 Dec 20;     [PubMed]
Zelner I,Matlow J,Hutson JR,Wax P,Koren G,Brent J,Finkelstein Y, Acute Poisoning During Pregnancy: Observations from the Toxicology Investigators Consortium. Journal of medical toxicology : official journal of the American College of Medical Toxicology. 2015 Sep;     [PubMed]
Stojiljković MP,Škrbić R,Jokanović M,Kilibarda V,Bokonjić D,Vulović M, Efficacy of antidotes and their combinations in the treatment of acute carbamate poisoning in rats. Toxicology. 2018 Sep 1;     [PubMed]
King AM,Aaron CK, Organophosphate and carbamate poisoning. Emergency medicine clinics of North America. 2015 Feb;     [PubMed]

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