Tuesday, July 29, 2014

Physostigmine: The Drug, The Dogma, and the Real Story

Physostigmine is a reversible cholinesterase inhibitor used in the management of antimuscarinic toxicity.  It differs from pharmacologically similar medications, such as neostigmine and pyridostigmine, due to its tertiary amine structure, which facilitates entry into the central nervous system.  By crossing the blood-brain barrier, we can expect it to be effective for reversal of both peripheral and central signs of the antimuscarinic toxidrome [1].


Inhibition of the cholinesterase enzyme will cause an increase of acetylcholine in the synapse of cholinergic nerve fibers.  As a result, efficacy related to reversal of antimuscarinic toxicity is associated with increased availability of the neurotransmitter at the receptors for competition with xenobiotics blocking those receptors.  In contrast to naloxone and flumazenil which work by direct inhibition of their respective receptors, the indirect mechanism of physostigmine leads to a somewhat complicated evaluation of its pharmacokinetic parameters.  The duration of action of receptor-based reversal agents would be expected to correlate well with the serum half-life of the drug; however, in the case of physostigmine, its duration is much longer and is likely better characterized by the half-life of cholinesterase inhibition.   A study evaluating the pharmacokinetics of physostigmine in patients with Alzheimer’s disease found that the half-life of cholinesterase inhibition (about 80 minutes) was five times that of the plasma half-life (approximately 16 minutes) [2]. Onset of action is delayed by several minutes because efficacy is dependent on accumulation of acetylcholine in the synapse rather than direct receptor blockade. 

An increase in acetylcholine does not come without risk.  We know from experience with other cholinesterase inhibitors (e.g., carbamate insecticides and organophosphates) that excess acetylcholine can be incredibly toxic.  When administered to patients without antimuscarinic toxicity, adverse effects of physostgimine include nausea, vomiting, and diaphoresis [2].  In the setting of overdose where multiple other medications may be contributing to the presentation of the patient, other consequences of acetylcholine may be more concerning.   Acetylcholine released from the vagus nerve binds to muscarinic receptors of the sinoatrial and atrioventricular nodes causing slowed conduction and the potential for bradycardia/bradydysrhythmias [3,4].  Seizures are common with certain cholinesterase exposures and seizure threshold appears lowered due to acetylcholine induced glutamate release [5].

Despite antidotal use dating back to the 1860s [6], recent use of the drug has been limited due to concern for potential adverse effects.  In 1980, a report was published by Pentel and Peterson detailing two cases of physostigmine administration complicated by asystole [7].  Both cases involved severe tricyclic antidepressant toxicity with seizures and significant blockade of cardiac sodium channels manifested by prolonged QRS duration on ECG and a relative bradycardia (both patients with heart rates of 75 beats/minute).  Of note, one patient had also ingested propranolol.  Each patient received physostigmine and subsequently developed bradycardia and asystole. 

So what happened in these patients?  Is this indicative of unpredictable and severe adverse effects related to physostigmine administration or are these expected effects related to increasing acetylcholine in the presence of severe sodium channel blockade?  Both patients had very severe conduction blocks and increasing acetylcholine concentrations in that scenario presumably slowed conduction even further.  The administration of physostigmine likely removed the protective effect of antimuscarinic tone that led to an increase in heart rate despite sodium channel blockade [8].  Additionally, the progression of seizures, severe conduction blocks, and bradycardia is consistent with the natural progression of severe tricyclic antidepressant toxicity resulting in fatalities [9].  It is possible that the patients in that report may have developed asystole even without the administration of physostigmine. 

Concern for seizures is another frequently cited rationale against the administration of physostigmine.  Although severe cholinergic crisis may cause seizures, this would be unlikely to happen in a healthy individual given a normal dose of physostigmine. In fact, this was not reported as an adverse effect in the pharmacokinetic study done in Alzheimer’s patients [2].  Because acetylcholine-induced glutamate release lowers the seizure threshold, it is not surprising that reports of “physostigmine-induced seizures” occur in the setting of overdose with eleptogenic medications [7, 10-11].  Mitigation of seizure risk can be accomplished with co-administration of benzodiazepines in these patients.  In fact, we often use adjunctive benzodiazepines along with physostigmine when neuromuscular excitation is present.

Another argument against physostigmine use is the belief that benzodiazepines are a safe alternative and can provide control of agitation while avoiding the potentially serious adverse effects.  A retrospective study [12] comparing these therapies in 52 patients found that physostigmine reversed delirium in 87% of patients and controlled agitation in 96%.  Benzodiazepines controlled agitation in 24% of patients but did not reverse delirium in any patients.  Time to recovery was shorter in patients treated with physostigmine first (12 hours versus 24 hours; p = 0.04).  Complications were statistically significantly higher in patients treated with benzodiazepines and included intubation, aspiration pneumonia, and delayed recovery.  Cholinergic adverse effects (diaphoresis, emesis, diarrhea, asymptomatic bradycardia, increased secretions) were reported in 11% of patients receiving physostigmine but none developed asystole or seizures.  Despite significant limitations related to the retrospective nature and small sample size, this study gives us data that benzodiazepines are unable to control delirium and may in fact be harmful in the management of antimuscarinic toxicity.

Determining when physostigmine use is warranted can be confusing due to the complex nature of the drug’s pharmacokinetic and pharmacodynamic interactions along with the strong sway of opinion that have marred debate regarding its use since the Pentel and Peterson case report [7] was published.  Due to the short serum half-life, there is often the impression that re-dosing the antidote will be needed and is likely to be frequent.  A retrospective study [13] evaluating this hypothesis found that only 31% of patients received multiple doses.  Interestingly, the longest time reported between doses was approximately 5.5 hours.  The investigators did not evaluate the effect of the initial physostigmine dose or severity of toxicity on the likelihood of receiving multiple doses.

Our toxicology consult service frequently utilizes physostigmine as an antidote and we have administered it in over 120 unique patient encounters since 2011.  We have had no serious adverse effects related to its administration.  It has been effective in reversing agitation/delirium associated with several medications including diphenhydramine, hydroxyzine, clozapine, and promethazine.  We have also found it useful for reversing the coma and delirium associated with cyclobenzaprine, quetiapine, and olanzapine.   Rapid administration has previously been related to adverse effects [1] and does not improve efficacy.  Our protocol involves administration of a 2 mg dose over 10 minutes; the dose is prepared by diluting a 2 mg ampule in a syringe containing 0.9% sodium chloride to a total volume of 10 mL.  We avoid use of physostigmine in patients with significant conduction blocks or those with bradycardia.

Physostigmine is an effective agent in the management of antimuscarinic toxicity and is safe when used appropriately.  Previous reports of asystole after administration have been misinterpreted as a serious and unpredictable side effect rather than an event that may be anticipated in selected patients (e.g. severe tricyclic antidepressant toxicity or those also ingesting a beta blocker).  The case report by Pentel and Peterson made no recommendations regarding the use of physostigmine; however, many clinicians have used the reported effects as a reason for avoiding its use altogether.  At the time of its publication, tricyclic antidepressant intoxication was much more common than it is now and may have called into question a positive risk-benefit analysis. I believe it is important to reconsider this analysis.  We know that severe tricyclic antidepressant toxicity is frequently manifested by rapid onset and progression of coma, seizures, conduction blocks, and hypotension; my conclusion from the oft-cited reports of asystole would be to avoid physostigmine in these patients.  We should be careful not to misinterpret the data presented as rationale for avoiding the use of physostigmine in all patients, as some may benefit from its administration.


Rachel Schult, Pharm.D.
Clinical Pharmacy Specialist, Toxicology
University of Rochester Medical Center
Rochester, New York

References:
  1. Howland M. Antidotes in Depth (A12): Physostigmine Salicylate. In: Nelson LS, Lewin NA, Howland M, Hoffman RS, Goldfrank LR, Flomenbaum NE. eds. Goldfrank's Toxicologic Emergencies, 9e New York, NY: McGraw-Hill; 2011:759-762.
  2. Asthana S, Greig NH, Hegedus L, et al.  Clinical pharmacokinetics of physostigmine in patients with Alzheimer's disease.  Clin Pharmacol Ther 1995; 58(3):299-309.
  3. Curry SC, Mills K, Ruha A, O'Connor AD. Chapter 13. Neurotransmitters and Neuromodulators. In: Nelson LS, Lewin NA, Howland M, Hoffman RS, Goldfrank LR, Flomenbaum NE. eds. Goldfrank's Toxicologic Emergencies, 9e New York, NY: McGraw-Hill; 2011: 191-194.
  4. Organophosphates. In: POISINDEX® System [Internet database]. Greenwood Village, Colo: Thomson Micromedex. Updated periodically.
  5. Collombet JM.  Nerve agent intoxication: recent neuropathophysiological findings and subsequent impact on medical management prospects.  Toxicol Appl Pharmacol 2011; 255(3):229-41.
  6. Nickalls RWD, Nickalls EA: The first use of physostigmine in the treatment of atropine poisoning. Anesthesiology. 1988; 43:776-779. 
  7. Pentel P, Peterson CD.  Asystole complicating physostigmine treatment of tricyclic antidepressant overdose.  Ann Emerg Med 1980; 9(11):588-90.
  8. Suchard JR.  Assessing physostigmine’s contraindication in cyclic antidepressant ingestions.  J Emerg Med 2003; 25(2):185-91.
  9. Kulig K, Rumack BH.  Physostigmine and asystole.  Ann Emerg Med 1981; 10(4):228-29.
  10. Knudsen K, Heath A.  Effects of self poisoning with maprotiline.  Br Med J (Clin Res Ed) 1984; 288(6417):601-3.
  11. Newton RW.  Physostigmine salicylate in the treatment of tricyclic antidepressant overdosage.  JAMA 1975; 231(9):941-3.
  12. Burns MJ1, Linden CH, Graudins A, et al.  A comparison of physostigmine and benzodiazepines for the treatment of anticholinergic poisoning.  Ann Emerg Med 2000; 35(4):374-81.
  13. Rosenbaum C, Bird SB.  Timing and frequency of physostigmine redosing for antimuscarinic toxicity.  J Med Toxicol 2010; 6(4):386-92.                                         

Editorial note:
Physostigmine is one of those drugs that has a very specific and clear indication with several contraindications, making it seemingly more dangerous than it really is. As the case with several drugs (e.g. droperidol, flumazenil, nitroprusside), bias associated with reporting of both successful treatment and complications associated with administration is clearly a factor when it comes to evaluating where these dogmas, as Rachel has described, have originated. One other confounding factor associated with this is the fact that back in the 1970s and 1980s when physostigmine began to gain a bad rap, clinicians did not understand and appreciate the wide range of complications associated with toxicity of tricyclic antidepressants, and as a result, goals for treatment were different than they are now. Although we do know better now, such ideas have affected clinical practice, as it was recently demonstrated that physostigmine is underutilized relative to benzodiazepines in managing anticholinergic toxicity. Prudent use of the drug is key, and when utilized in this manner, it holds much value as an antidote in the emergent and critical setting.

--Nadia Awad, Pharm.D., BCPS (Nadia _EMPharmD)