Physostigmine or Rivastigmine for Anticholinergic Toxicity

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 effects^2–4. 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 alone^5,6. 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 drugs^7,8. 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 physostigmine^12–15. 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.