Does this old chestnut of a mnemonic describe patients you have seen in the emergency room? These symptoms outline anticholinergic poisoning, a possible result of some plants and many drugs, one of the most common being diphenhydramine overdose.
MANIFESTATIONS OF ANTICHOLINERGIC POISONING
The peripheral manifestations of the blockade of muscarinic receptors include warm, flushed skin, dilated pupils, blurry near vision and intolerance of bright light, dry axilla and oral membranes, urinary retention and quiet bowel, hyperthermia, and tachycardia with elevated blood pressure. Central manifestations include altered mental status, agitation, combativeness, confusion, delirium, hallucinations, seizures, and coma. Depending on the agent and dose, the poisoning can last for days.
RIVASTIGMINE TO THE RESCUE WHEN PHYSOSTIGMINE IS “UN-OBTAIN-IUM”
Pharmaceutical cholinesterase inhibitors temporarily inactivate acetylcholinesterase, thus boosting the synaptic presence of acetylcholine and overcoming the blockade induced by the anticholinergic agent. Physostigmine was the agent of choice for anticholinergic delirium because it rapidly calms a violently-agitated patient within 5-15 minutes of IV administration.
However, physostigmine has been subject to recurring nationwide shortages for several years, and the sole US manufacturer eventually ceased production altogether. This prompted interest in rivastigmine, a centrally-acting cholinesterase inhibitor used for Alzheimer’s dementia, as an off-label therapeutic substitute. Rivastigmine has shown favorable results when given either orally or transdermally, alone or in combination with physostigmine.
PHYSOSTIGMINE SUPPLY SHORTAGES MAY BE COMING TO AN END
Recently, another company, Healthfirst, purchased the physostigmine product from the original manufacturer and is resuming production. In addition, in September 2023, the FDA allowed import and distribution of a German physostigmine pharmaceutical, Anticholium injection, by one US company, Provepharm, and its distributor, Direct Success.
Anticholium has some differences from the US FDA-approved product, most notably the concentration. US facilities are accustomed to physostigmine injection 1 mg/mL in a 2-mL ampule (2 mg total per ampule), and the Anticholium product is supplied as 0.4 mg/mL in a 5-mL ampule (also 2 mg total).
The package is not marked with the legend “Rx only,” although it is intended to be prescription only. The barcode may not scan accurately in US systems. It is recommended that the barcode be entered manually and then confirmed that if the barcode is scanned, the system gives accurate information.
SUGGESTED USE OF PHYSOSTIGMINE AND/OR RIVASTIGMINE FOR ANTICHOLINERGIC DELIRIUM
Consider physostigmine and/or rivastigmine for severe central or peripheral anticholinergic symptoms (violent agitation, seizures, distressing hallucinations, hypertension, arrhythmias) that are not responding to standard therapy. They should not be used just to keep a patient awake.
- IV Physostigmine is still the drug of choice, if available.
Caution: There is increased risk of severe complications (seizures, ventricular arrhythmias, bradycardia, and asystole) in patients with drug-induced widening of the QRS caused by sodium channel block. This combination of anticholinergic symptoms and sodium channel blockade is seen most often in diphenhydramine and tricyclic antidepressant poisoning. Physostigmine use should be delayed until the QRS can be narrowed with sodium bicarbonate bolus and infusion.
- Teen-Adult dosing: Under continuous cardiac monitoring, 0.5 to 1 mg over 5 to 10 minutes by slow IV to reduce the risk of serious adverse effects. Repeat if necessary in 10-15 minutes until delirium is improved or 2 mg total dose is reached during the first hour.
Physostigmine has a short duration of action compared to most anticholinergic toxins. Although sometimes a single dose seems to “reset” the CNS, repeated bolus dosing is often necessary.
- IV Physostigmine, followed by maintenance dosing of transdermal OR oral rivastigmine
If physostigmine is available in limited quantity, therapy can be rapidly initiated with IV physostigmine. If physostigmine was effective, start 24-hours of maintenance dosing with rivastigmine immediately afterwards to prevent recurrence of anticholinergic delirium.
- In teens and adults, it can be given either orally (3-6 mg every 12 hours x 2), or as a 24-hour transdermal patch applied to the upper back (9.5 or 13.3 mg/24 hr applied once).
- Rivastigmine oral initiation and oral maintenance dosing
Rivastigmine oral capsule or solution can be used to initiate therapy if no physostigmine is available. This dosing regimen is suggested by the poison center. Others have been described.
Teen-Adult suggested initiation regimen of oral rivastigmine:
- 3 mg capsule or oral solution by mouth every 2 hours until symptoms are controlled or a maximum of 12 mg is reached (FDA-approved maximum daily dose).
If control of agitated delirium or other symptoms is not reached two hours after the last dose, reassess the diagnosis and, if appropriate, attempt control with additional diazepam, dexmedetomidine, or antipsychotic.
- STOP administration if signs of cholinergic excess develop (e.g., rhinorrhea, salivation, nausea, vomiting, bradycardia.)
- Maintenance dosing of rivastigmine after the initial loading dose is suggested as 3-6 mg every 12 hours for 24 hours.
- Rivastigmine concurrent oral plus transdermal dosing
For Teen-Adult patients, rivastigmine therapy can be given with one initial oral dose as above and concomitant placing of a transdermal patch (9.5 or 13.3 mg/24 hr) applied once on the upper back.
EXCESSIVE DOSING OF PHYSOSTIGMINE AND/OR RIVASTIGMINE
Inappropriate use due to misdiagnosis or excessive doses beyond what is necessary to counteract anticholinergic effects can lead to the opposite problem – symptoms of cholinergic excess. These include gastrointestinal distress, heavy secretions, bradycardia, and muscle fasciculations, and weakness. Atropine should be available at the bedside in case the patient develops iatrogenic cholinergic poisoning.
For patient-specific guidance on possible anticholinergic toxicity and treatment, please contact the Missouri Poison Center at 1-800-222-1222. Our specially trained nurses, pharmacists, and toxicologists can offer information on physostigmine and rivastigmine and provide the most up-to-date information regarding exposures and treatment.