Physostigmine or Rivastigmine for Anticholinergic Toxicity

Mnemonic for Anticholinergic Symptoms

Take Home Points

  • Physostigmine is useful in the treatment of anticholinergic toxicity and can potentially prevent a patient from being intubated and receiving large amounts of sedatives

  • Rivastigmine is a potentially safe and effective antidote in the setting where physostigmine is unavailable

  • The FDA has allowed for the temporary importation of Anticholium® (physostigmine salicylate) due to physostigmine shortages

  • Call the Utah Poison Control Center at 1-800-222-1222 at any time 24/7 for assistance in managing anticholinergic toxicity and administering physostigmine or rivastigmine

Anticholinergic Toxicity

Anticholinergic toxicity is caused by the excessive blockade of acetylcholine at muscarinic receptors, a neurotransmitter that plays a crucial role in the nervous system1. While the term antimuscarinic is more appropriate, as these drugs do not block nicotinic acetylcholine receptors, anticholinergic toxicity is more commonly used. Anticholinergic drugs are commonly used for medical conditions, such as allergies, motion sickness, and Parkinson's disease. Examples of classes of medications with anticholinergic properties include antihistamines (such as diphenhydramine), tricyclic antidepressants, and sleep aids. 

Exposure to an excessive amount of anticholinergic drugs or substances with anticholinergic effects blocks parasympathetic muscarinic tone, eventually leading to an overabundance of sympathetic activity. Symptoms may include blurred vision, confusion, hallucinations, delirium, dry skin and mouth, increased heart rate, cardiac abnormalities, urinary retention, pupil dilation, hyperthermia, and, in severe cases, seizures, or coma1.

Management of anticholinergic toxicity involves decontamination, such as administration of activated charcoal to prevent further absorption of the drug, and medications like physostigmine to counteract the anticholinergic effects2–4. Physostigmine may improve confusion, agitation, hallucinations, and delirium by enhancing cholinergic neurotransmission in the central nervous system.

Additional management of non-anticholinergic symptoms includes stabilization of the airway, breathing, and circulation, monitoring for sinus tachycardia, treating prolonged QRS intervals with sodium bicarbonate, and treating seizures with benzodiazepines. It's crucial to seek medical attention promptly if someone is suspected of having anticholinergic toxicity to prevent complications and ensure appropriate treatment.

Physostigmine Salicylate

Physostigmine salicylate is an acetylcholinesterase inhibitor used for anticholinergic toxicity reversal. This medication may be useful in patients exhibiting significant central anticholinergic toxicity that need additional care beyond supportive care alone5,6. Physostigmine is indicated to reverse the effect upon the central nervous system caused by clinical or toxic dosages of drugs capable of producing the anticholinergic toxidrome. The mechanism of action of physostigmine in anticholinergic toxicity is the inhibition of acetylcholinesterase, the enzyme responsible for breaking down acetylcholine. By doing so, it increases the concentration of acetylcholine in the synaptic cleft, thereby counteracting the effects of anticholinergic drugs7,8. Compared to benzodiazepines for anticholinergic poisoning-induced delirium and agitation, physostigmine has been shown to be more effective and safer9. Literature also indicates fewer adverse drug reactions. 

Physostigmine Shortages and Alternatives

Rivastigmine: Physostigmine has undergone drug shortages in the United States since 2022. As of February 2023, Akorn Pharmaceuticals, the sole producer of physostigmine in the United States, shut down, further exacerbating the shortage issue. In response, some medical facilities and Poison Control Centers recommend using rivastigmine, a long-acting acetylcholinesterase inhibitor. Rivastigmine is available in oral and transdermal patch formulations. Like physostigmine, it can cross the blood-brain barrier to reverse central anticholinergic effects. 

Anticholium®: Due to the ongoing physostigmine shortage, the FDA has allowed for the temporary importation of Anticholium® (physostigmine salicylate) 0.4 mg/mL 5 mL ampules from Germany10. Anticholium® is being distributed by Provepharm via its distributor Direct Success. Orders may be placed by hospital buyers by contacting Direct Success. More information can be found on the FDA website https://www.fda.gov/media/173483/download?attachment.  

Physostigmine and Rivastigmine Indications

Physostigmine and rivastigmine are recommended for control of anticholinergic delirium in adults and children. Central signs of anticholinergic toxicity include: delirium, picking behavior, easily startled/frightened, and incoherent speech. Peripheral signs include tachycardia, flushing, dry mouth, and urinary retention. 

Physostigmine and Rivastigmine Safety

Observational studies suggest that administering physostigmine for known or suspected anticholinergic toxicity is safe, with minimal complications when appropriately administered7. In a retrospective study with 191 subjects, the administration of physostigmine demonstrated a favorable safety profile (95.3% had no documented adverse effects) and frequently improved or resolved anticholinergic delirium when given in doses below 2mg7. To note, physostigmine use is contraindicated in patients with a wide QRS > 100 msec, R wave in lead aVR > 3 mm, and in patients with an ingestion of tricyclic antidepressants. The contraindication of use of physostigmine in patients with a tricyclic antidepressant overdose is a result a 1980 case report that described cardiac arrest in two adults with tricyclic antidepressant overdose following physostigmine administration. Physostigmine may worsen conduction disturbances, decrease cardiac output, and cause bradyarrythmias or asystole. These cardiac disturbances may potentially exacerbate life-threatening cardiotoxicity as described in the case report. The two patients described had the presence of a widened QRS complex, first-degree AV block, asystole, and/or bradycardia post administration of IV physostigmine11. Notably, these patients were not suffering from anticholinergic delirium and instead needed TCA toxicity specific treatments such as vasopressors, benzodiazepines, and sodium bicarbonate.

Use of rivastigmine in anticholinergic overdose case reports support that rivastigmine may be a safe and effective alternative to physostigmine12–15. In one case report, a patient received 12mg total in a span of 24 hours and had complete resolution of symptoms and developed no adverse effects or recurrent symptoms of anticholinergic toxicity. Within the two hours the patient remained slightly confused and showed significant improvement in agitation (from RASS +3 to RASS +1). In a study with 22 patients experiencing anticholinergic delirium, all patients received rivastigmine patch (median dose 13.3 mg), and almost 70% of patients also received oral rivastigmine (median dose 6 mg)12. No patients experienced an adverse event attributed to rivastigmine. Although data are limited, current reports support that rivastigmine may be a safe and effective alternative to physostigmine in the time of a shortage12. 

Additionally, the Utah Poison Control Center did a retrospective review of 30 patients who received rivastigmine to treat anticholinergic toxicity from January 2021 to March 2023 and observed rivastigmine to be safe and potentially beneficial in treating anticholinergic toxicity. Every patient received oral rivastigmine and 2 patients received transdermal rivastigmine in combination with oral rivastigmine. Almost 67% of patients demonstrated symptom improvement with one half the patients experiencing symptom improvement within 4 hours16. 

Physostigmine Dosing17
  • Adult: IV: 1 mg slowly over 5 minutes 
    • Stop infusion if heart rate is < 70
    • If there is a partial response, a second 1 mg dose may be given with same precautions
    • Onset: 2 minutes
    • Duration: 45-60 minutes
    • May repeat as needed every 1-2 hours 
  • Pediatric: IV: 0.02 mg/kg slowly over 5 minutes
    • Stop infusion if heart rate is < 70
    • If there is a partial response, a second 0.02 mg/kg mg dose may be given with same precautions
    • Max dose: 0.5 mg/dose
    • May repeat as needed every 1-2 hours 
  • Most patients receive about 2 mg
  • Generally a single dose or a short duration of treatment (<6.5 hours) is sufficient

Rivastigmine Dosing 

  • Delirious patients may be unable to take rivastigmine capsules
  • Treatment with rivastigmine is recommended until resolution of CNS symptoms
  • Oral dose of 3-6 mg every hour until resolution of symptoms, max 12 mg/day13,14,18,19 
    • Recommended dosing: 6 mg, give additional 3 mg orally every hour as needed for ongoing delirium
    • Swallow capsules whole, do no administer if patient is not able to swallow 
    • Onset: 1 hour
    • Duration: 10 hours
  • Patch dose of  4.6 mg, 9.5 mg, or 13.3 mg20
    • Adults: 9.5 mg for most patients is appropriate
      • > 100 kg patient: consider starting with 13.3 mg patch
    • Pediatric, < 35kg: 4.6 mg
    • Do not cut or alter patch
    • Remove after 24 hours
    • Consider applying patch on patient’s back where it is more difficult for the patient to remove
    • Onset: 8 hours
    • Duration: 10 hours
  • May consider using both oral and transdermal rivastigmine together if patient is no longer able to take oral doses or to avoid repeated oral doses

Lab Ordering and Pitfalls
  • Signs of  the anticholinergic toxidrome include increased blood pressure and pulse, dilated pupils, altered mental status with delirium—garbled speech/word salad, “picking at self” behavior, dry/flushed skin, and urinary retention
  • Perform electrocardiogram (ECG) to rule out conduction system poisoning that affects the QRS or the QTc intervals. It is crucial all patients get an ECG with anticholinergic toxicity
  • CBC, electrolytes, Mg, CK, glucose, CT head, and/or lumbar puncture may aid in the diagnosis of patients with altered mental status determined not to be due to an anticholinergic toxidrome
  • If the patient had severe agitation, check electrolytes and creatinine kinase (CK) level to evaluate for possible rhabdomyolysis
  • Check acetaminophen and aspirin levels, as many cold remedies include these medications in addition to diphenhydramine
  • Pitfalls in the interpretation of toxicology panel: TCA may come back positive in diphenhydramine overdose; however this is a false positive21

Call the Utah Poison Control Center at 1-800-222-1222 at any time 24/7 for assistance in managing known or suspected anticholinergic poisonings.

References:
  1. Broderick ED, Metheny H, Crosby B. Anticholinergic Toxicity. In: StatPearls. StatPearls Publishing; 2023. Accessed November 17, 2023. http://www.ncbi.nlm.nih.gov/books/NBK534798/
  2. Antihistamines and Decongestants | Goldfrank’s Toxicologic Emergencies, 11e | AccessPharmacy | McGraw Hill Medical. Accessed November 17, 2023. https://accesspharmacy.mhmedical.com/content.aspx?bookid=2569&sectionid=210272449
  3. Green R, Sitar DS, Tenenbein M. Effect of anticholinergic drugs on the efficacy of activated charcoal. J Toxicol Clin Toxicol. 2004;42(3):267-272. doi:10.1081/clt-120037426
  4. Thomas SHL. Antihistamine poisoning. Medicine (Baltimore). 2016;44(3):141-142. doi:10.1016/j.mpmed.2015.12.002
  5. Dawson AH, Buckley NA. Pharmacological management of anticholinergic delirium - theory, evidence and practice. Br J Clin Pharmacol. 2016;81(3):516-524. doi:10.1111/bcp.12839
  6. Beaver KM, Gavin TJ. Treatment of acute anticholinergic poisoning with physostigmine. Am J Emerg Med. 1998;16(5):505-507. doi:10.1016/s0735-6757(98)90003-1
  7. Arens AM, Shah K, Al-Abri S, Olson KR, Kearney T. Safety and effectiveness of physostigmine: a 10-year retrospective review<sup/>. Clin Toxicol Phila Pa. 2018;56(2):101-107. doi:10.1080/15563650.2017.1342828
  8. Nguyen TT, Armengol C, Wilhoite G, Cumpston KL, Wills BK. Adverse events from physostigmine: An observational study. Am J Emerg Med. 2018;36(1):141-142. doi:10.1016/j.ajem.2017.07.006
  9. 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;35(4):374-381. doi:10.1016/S0196-0644(00)70057-6
  10. Drug Shortage Detail: Physostigmine Salicylate Injection. Accessed November 15, 2023. https://www.ashp.org/Drug-Shortages/Current-Shortages/Drug-Shortage-Detail.aspx?id=721
  11. Pentel P, Peterson CD. Asystole complicating physostigmine treatment of tricyclic antidepressant overdose. Ann Emerg Med. 1980;9(11):588-590. doi:10.1016/s0196-0644(80)80232-0
  12. Greene SC. Rivastigmine Use in the Treatment of Antimuscarinic Delirium. J Med Toxicol Off J Am Coll Med Toxicol. 2023;19(3):284-287. doi:10.1007/s13181-023-00947-1
  13. Hughes AR, Moore KK, Mah ND, et al. Letter in response to Rivastigmine for the treatment of anticholinergic delirium following severe procyclidine intoxication. Clin Toxicol Phila Pa. 2021;59(9):855-856. doi:10.1080/15563650.2020.1869757
  14. Van Kernebeek MW, Ghesquiere M, Vanderbruggen N, Verhoeven E, Hubloue I, Crunelle CL. Rivastigmine for the treatment of anticholinergic delirium following severe procyclidine intoxication. Clin Toxicol Phila Pa. 2021;59(5):447-448. doi:10.1080/15563650.2020.1818768
  15. Fratta KA, Ginder M, Haggerty DA. Oral and Transdermal Rivastigmine for the Treatment of Anticholinergic Delirium: A Case Report. J Emerg Med. 2023;65(4):e366-e368. doi:10.1016/j.jemermed.2023.06.008
  16. Lambson J, Hinckley P, Moss M. Rivastigmine to treatanticholinergic toxicity following drugoverdose. Clin Toxicol. 2023;61:22-23.
  17. DailyMed - PHYSOSTIGMINE SALICYLATE injection. Accessed November 17, 2023. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9a448a78-356c-50f7-e053-2995a90adefa
  18. Hoffman L. AHEAD OF PRINT: Rivastigmine Steps in During Physostigmine Shortage. Emerg Med News. Published online May 18, 2021. Accessed November 17, 2023. https://journals.lww.com/em-news/blog/breakingnews/pages/post.aspx?PostID=588
  19. 020823s036,021025s024lbl.pdf. Accessed November 17, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/020823s036,021025s024lbl.pdf
  20. 022083lbl.pdf. Accessed November 17, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/022083lbl.pdf
  21. Matos ME, Burns MM, Shannon MW. False-Positive Tricyclic Antidepressant Drug Screen Results Leading to the Diagnosis of Carbamazepine Intoxication. Pediatrics. 2000;105(5):e66. doi:10.1542/peds.105.5.e66

Author: Kristine Jermakian, PharmD, PGY2 Pharmacy Resident, Intermountain Primary Children's Hospital

Poison Control