How do anticholinergic toxidromes present? Why have you not used physostigimine for anticholinergic-induced delirium? What alternatives are there when physostigmine isn't available?
Hello there Pharmers and Friends, Mark with PHARMWYZE. I'm a board-certified emergency medicine pharmacist that makes clinical pharmacotherapy content on the social medias. Welcome to the Code Blue Debrief: A Clinical Pharmacotherapy YouTube & Podcast Series.
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The topic of our today's episode will be on anticholinergic poisonings and reversal agents
When I was a second year resident in emergency medicine, the U.S. Food and Drug Administration released a warning in September 2020 regarding the dangers of taking more than the recommended doses for over-the-counter Benadryl® (diphenhydramine) allergy medication. COVID was a crazy time.
Reports of adolescents overdosing on diphenhydramine has drawn national attention. Teenagers and young adults have been participating in the “Benadryl Challenge” on TikTok, where they post videos of themselves taking large quantities of diphenhydramine. This fad was brought into the media spotlight in more recent months, but diphenhydramine has been one of the most common intentional ingestions even prior to the trend. You can check out the article I wrote for the Utah Poison Control Center, the link is in the description.
Anticholinergics are easily accessible as OTC sleepaids and allergy medications. Don't forget about prescribed anticholinergics, such as hydroxyzine, and those that contains minor properties, including cyclobenzaprine. 'Let's review the anticholinergic toxidrome, in addition to primary and secondary pharmacologic culprits.
Pathophysiology
For a little flashback to pharmacology 101, we associate the sympathetic nervous system with a flight or flight response, while the parasympathetic pathway is deemed as rest and digest. Neurotransmitters pertaining to the parasympathetic nervous system are acetylcholine, nicotinic, and muscurinic. Organophosphates cause cholinergic excess, leading to toxicities with salivation, lacrimation, urination, defecation, and emesis, or SLUDGE.
This gives you some context since the anticholinergic toxidrome is the complete opposite. Poisonings can be centrally and peripherally acting. In the periphery, symptoms include hypertension, tachycardia, decreased bowel motility, urinary retention, and dry mucosal membranes. Progressive symptoms associated with central toxicities include confusion, agitation, delirium, hallucinations, seizures, and then coma. You'll commonly hear "blind as a bat, mad as a hatter, dry as a bone, red as beet, hot as a hare, and full as a flask" to remember the anticholinergic toxidrome.
When we think of anticholinergics, diphenhydramine often comes to mind first since it is available over the counter. Other antimuscurinics that do not require a prescription include doyxlamine, ceterizine, loratadine, and meclizine. The older generation antihistamines, such as diphenhydramine and doxylamine, are more for used as sleepaids given their centrally-acting sedative effects.
Polypharmacy has been an ongoing concern in medicine. Medications have many considerations with interactions, metabolism, and elimination as we age. Anticholinergic toxicities are often precipitated unknowingly from secondary medications. Medications with anticholinergic properties are antidopamanergics, including quetiapine and olanazpine, as well as tricyclic antidepressants and cyclobenzaprine. With any concerns for poisonings, contact the poison control center and consult your pharmacist.
Antidote: Physostigmine
Physostigmine is a reversal agent for anticholinergic toxicities. By inhibiting acetylcholinesterase, increased acetylcholine becomes available at the synapses. As a tertiary amine, it readily crosses the blood brain barrier to reverse the effects of antimuscurinic poisonings.
It is dosed at 0.5 to 2 mg and may be repeated every 10 to 30 minutes as needed. Administer no faster than 1 mg/min to minimize risks of bradycardia, respiratory distress, and seizures. Physostigmine has a short half life with a duration of an hour. Severe ingestions will require repeat doses or continuous infusion. Start infusion at 1 mg/hour titrated every 30 minutes to clinical effect. The onset is within 5 minutes IV, and 20 when given IM.
I'm all for anyone who wants to hop on the Ativan ride for agitation. However, physostigmine will be the agent of choice with antimuscurinic poisonings. Benzodiazepines do not address the underlying toxic mechanism, while increasing the risk of oversedation and respiratory depression with copious use for anticholinergic-induced delirium. Benzodiazepines are considered first for most undifferentiated agitation, but preference to physostigmine should change with delirium as patient history, examiniation, and overall workup point towards anticholinergic toxicity.
The fear of physostigmine comes from early case reports that resulted in two deaths afteroverdosing on tricyclic antidepressants and receiving the physostigmine. This led to the black-box warning of physostigmine being contraindicated with concerns for TCA ingestions. Physostigmine should be avoided in patients with a widened QRS, AV block, or bradycardia. Under these circumstances, physostigmine may worsen conduction disturbances, and cause bradyarrythmias or asystole. Precipitation of seizures is another concern for physostigmine. This can be avoided by diluting each physostigmine dose of 0.5 to 1 mg in 10 mL D5W or normal saline and administering as a slow IV push over 2 to 5 minutes. Benzodiazepines will be our treatment option specifically for seizures. Physostigmine addresses delirium.
Wang et al. performed blinded, randomized trial in 2021 with patients presenting with anticholinergic toxidrome. They included patients 10 to 17 years old, at least one and two peripheral antimuscurinic symptoms, delirium, and moderate agitation. Patients were randomized to lorazepman 0.05 mg/kg bolus, followed by a 4-hr saline infusion or 0.02 mg/kg bolus followed by 4 hr physostigmine infusion at 0.02 mg/kg/hr. From their analysis, physostigmine was super to lorazepam in controlling antimuscarinic delirium and agitation. Furthermore, they did not detect any serious adverse events.
In 2015, Watkins and colleagues conducted a retrospective analysis of the Toxiciology Investigators Consotrium registry that medical toxicologist contribute their data to. They identified patients with an anticholinergic toxidrome, agents received including benzodiazepines and antipsychotics, and classifieds them into treatment groups. From their findings, patients with anticholinergic toxicity were more likely to receive benzodiazepines than physostigmine. Those patients who received only physostigmine had a significantly lower rate of intubation. It was more commonly used in primary anticholinergic presentations than mixed or unknonw presentations.
Physostigmine is an awesome drug for anticholinergic-induced delirium. Although, we've been undergoing supply and demand issues. The manufacturer recently went bankrupt and shut down their facility, leaving no manufacturer on the market available to make physostigmine.
We were left with limited options to treat anticholinergic toxicities and resorted to uncommon alternatives. An example would be rivastigmine orally or transdermally, which has shown to be effective in treating anticholinergic poisonings with ongoing supply issues. Just recently on October 31st, 2023, the FDA released a statement that there would be a temporary iomportation available for injectable physostigmine from Provepharm in Germany.
You can recall the anticholinergic toxidrome with"blind as a bat, mad as a hatter, dry as a bone, red as beet, hot as a hare, and full as a flask" Physostigmine is the preferred agent for anticholinergic-induced delirium. It is dosed at 0.5 to 2 mg and may be repeated every 10 to 30 minutes as needed. Administer no faster than 1 mg/min to minimize risks of bradycardia, respiratory distress, and seizures. Physostigmine has a short half life with a duration of an hour. Severe ingestions will require repeat doses or continuous infusion. Big pharma cannot figure out supply issues with all that money they're making.
As with any other medication in your drug bank, know what your currently have available and important therapies on shortage. This may require you to think outside of the box and to become familiar with with the limited evidence, if any. It seems that are physostigmine issues are temporarily fixed for now, but let me know in the comments below, what are your thoughts for rivastigmine as an alternative to physostigmine?
I appreciate you for staying to the end of this episode. Sending you some positive vibes with the recent negative global events. If you enjoyed the content today, give the video a thumbs up for more, check out my pharmacotherapy posts on the social medias, and I hope you learned something new.
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References
Newton RW. JAMA . 1975 Mar 3;231(9):941-3. Pentel P, Peterson CD. Ann Emerg Med . 1980 Nov;9(11):588-90. Wang GS et al. Clin Toxicol (Phila). 2021 Aug;59(8):698-704. Watkins JW et al. J Med Toxicol. 2015 Jun;11(2):179-84. Fratta KA, Ginder M, Haggerty DA. The Journal of Emergency Medicine, Vol. 65, No. 4, pp. e366–e368, 2023 McCoy CE, Honda R. J Educ Teach Emerg Med. 2023 Jan 31;8(1):S25-S47. Elkhazeen A et al. J Forensic Sci . 2023 Jan;68(1):339-342. Nishtala PS, Salahudeen SJ, Hilmer SN. Expert Opin Drug Saf . 2016 Jun;15(6):753-68. https://www.fda.gov/drugs/drug-shortages/october-31-2023-temporary-importation-available-physostigmine-injection https://www.ashp.org/drug-shortages/current-shortages/drug-shortage-detail.aspx?id=721&loginreturnUrl=SSOCheckOnly
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