Physostigmine is a tertiary amine, and a reversible cholinergic medication most commonly used in the management and treatment of antimuscarinic toxicity and glaucoma. Physostigmine originates from the Calabar bean, widely found in the African tropics.[1][2] Although small in size, it's fatalness was first discovered by Sir Robert Christison in 1855. A few decades later, in 1863, Sir Thomas Richard Fraser, wrote his thesis on the medicinal uses of physostigmine. From 1863 to this day, there has been extensive research done on the applications of physostigmine, examining its use in the treatment of glaucoma to its use in the treatment of septic shock.[1][3]

Physostigmine salicylate has FDA approval for use in the treatment of glaucoma, as well as the treatment of anticholinergic toxicity. It is useful to treat the central nervous system effects of anticholinergic toxicity due to its ability to cross the blood-brain-barrier.[4] The symptoms associated with anticholinergic toxicity are delirium, tachycardia, mydriasis, urinary retention, dry skin, and ileus. 

Concerning the treatment of glaucoma, physostigmine increases the levels of acetylcholine available for the ciliary muscle of the eye to contract. This increase results in increased aqueous humor flow and a decrease in intraocular pressure. Due to its increased side effects, medications with fewer side effects are preferable for the treatment of glaucoma.[1][5]

Recent studies have examined the use of physostigmine in systemic inflammation, sepsis, and nerve gas exposure. A randomized, double-blind placebo-controlled monocentric pilot trial performed between 2015 and 2017 with 20 enrolled patients looked at the effects of physostigmine in patients following intra-abdominal infections leading to septic shock. There was no statistical significance in the outcome between the two groups of placebo (0.9% sodium chloride) and physostigmine salicylate. The research found treatment with physostigmine salicylate to be feasible and safe. Future research looking at a large sample size is necessary to assess the effects of physostigmine on recovery from septic shock.[3] A study published in 2018 proposed using physostigmine loaded liposomes to protect against nerve gas exposure. Nerve gas commonly affects acetylcholinesterase by amplifying its action. Physostigmine can reversibly bind to acetylcholinesterase and block the effects of nerve gas. Liposomes were used in this study to prolong the half-life of physostigmine, which usually has a half-life of 23 minutes.[6][7] 

Physostigmine functions as a cholinergic medication by increasing the amounts of acetylcholine present at cholinergic synapses in the central and peripheral nervous systems. This medication inhibits the actions of acetylcholinesterase and butyrylcholinesterase, enzymes that normally break down acetylcholine.[8] Through this mechanism, acetylcholine accumulates at synapse sites of muscarinic or nicotinic receptors, triggering action potentials. This action leads to the muscarinic receptor effects of decreased pupil size, increased aqueous humor production, increased salivation, increased gastrointestinal secretions, increased urination, and sweating.[4] Nicotinic effects are those affecting striated muscle or sympathetic ganglia. Symptoms consist of cramps, fasciculations, twitching, weakness, elevated blood pressure, and tachycardia. Central nervous system effects are ataxia, and convulsions eventually leading to a coma.[5]

Administration of Physostigmine

For anticholinergic toxicity:

• Adults - Intramuscular or Intravenous: Start initially at 0.5 mg to 2 mg, with a minimum delay of at least 10 to 30 minutes before dosing if symptoms persist and are severe, with the absence of cholinergic signs. Infuse at a rate of 1 mg/minute in adults.
• Pediatric - Intramuscular or Intravenous: Start at 0.02 mg/kg, with a maximum dose of 0.5 mg/dose, 2 mg total; repeated every 5 to 10 minutes if symptoms persist and are severe, with the absence of cholinergic signs. Infuse at a rate no faster than 0.5 mg/minute in the pediatric population. 

For non-depolarizing neuromuscular blockade reversal:

• Adults - Intramuscular or Intravenous: Start initially at 0.5 mg, with a minimum delay of at least 10 to 15 minutes before re-dosing, up to a maximum dose of 2 mg in the first hour.[6] Infuse at a rate no faster than 1mg/minute in adults. 
• Pediatric - Intramuscular or Intravenous: Start initially at 0.01 mg/kg to 0.02 mg/kg in children, with a minimum delay of at least 10 to 15 minutes before re-dosing, up to a maximum dose of 2 mg in the 1st hour.[6] Infuse at a rate no faster than 0.5 mg/minute in the pediatric population.

Important note: When dosing with physostigmine, keep atropine available for any severe cholinergic symptoms. 

Significant adverse effects seen with the use of physostigmine are rarely reported and are most commonly related to overdose or seen in patients who have contraindications. 

Severe adverse effects:

• Cholinergic crisis 
• Bradycardia 
• Hypotension
• Seizures/hallucinations
• Anaphylaxis - especially in those with salicylate/sulfite allergies
• Respiratory depression 
• Cardiac arrest 

Common reactions:

• Nausea/vomiting 
• Diarrhea 
• Abdominal cramps 
• Lacrimation 
• Dyspnea
• Miosis
• Sweating 

In a literature review looking at 161 articles, and a total patient population of 2299; adverse effects from physostigmine occurred in 415 patients. These adverse effects mainly consisted of hypersalivation in 206 patients and nausea and vomiting in 96 patients. Patients who had seizures consisted of 15. Symptomatic bradycardia occurred in eight patients, of which three patients had bradycardic-asystolic arrests. Ventricular fibrillation occurred in one patient, who had an underlying coronary artery disease.[4]

Contraindications for physostigmine use include the presence of:

• Pulmonary disease-causing bronchoconstriction of the airways such as asthma
• Gangrene
• Diabetes
• Cardiovascular disease
• Gastrointestinal or urogenital tract obstruction
• Angle-closure glaucoma
• Coexisting medications with choline esters and depolarizing neuromuscular blockers or a salicylate/sulfite allergy

Caution is necessary when administering to patients with bradycardia, vagal tone increase, peptic ulcer disease, gastroesophageal reflux disease, hypotension, hyperthyroidism, and those with seizure disorders. 

Patients with QRS prolongation on EKG or those with a history of overdose with QRS prolonging medications should not receive physostigmine.[4]