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By Aaron Schneir MD
Physostigmine is a reversible acetylcholinesterase inhibitor capable of temporarily reversing the effects of antimuscarinic agents. It was first derived from a plant in Africa, the West Calabar Bean, where it was used in trials of witchcraft. Physostigmine has been used both diagnostically and therapeutically in the management of poisoned patients. Primarily because of occasional complications associated with physostigmine administration, its use remains controversial.
30-year-old male presents to the emergency department (ED) after being found wandering around outside of a mental health clinic. He is transported by paramedics to the ED. The patient is mumbling incoherently, picking at a button on his shirt and is unable to provide any history. His vital signs are the following BP-130/70 mmHg, P-114, R-16, T(rectally)- 100.7 F°. Physical examination reveals a supple neck, dry oropharynx, no palpable thyroid, tachycardia, decreased bowel sounds and dry axilla. He is disoriented to all questions and occasionally answers with incoherent mumbling speech. Although he moves all extremities equally, he does not follow any commands. Bedside blood glucose is normal and the cardiac monitor reveals sinus tachycardia with a normal qrs width. Insertion of a foley catheter drains 1000 cc of yellow urine.
A total of 2 mg of physostigmine is administered intravenously over a period of ten minutes leading to complete reversal of the patient’s delirium. The patient is now completely oriented and able to follow all commands. After requesting a drink of water for his dry mouth he reports that he had ingested a large amount of benztropine (Cogentin) in a suicide attempt earlier that day and denies ingestion of other medications. He has a history of schizophrenia but has been noncompliant with his other medications. He has no other medical problems and is not allergic to any medications. Approximately 30 minutes after the physostigmine was administered the patient becomes progressively delirious again and he begins to mumble incoherently and pick at things again.
Serum acetaminophen and salicylate levels are undetectable and routine serum chemistries and creatinine kinase (CPK) arenormal. The patient is admitted to the hospital and remains delirious for 2 days. No further physostigmine is administered. On the morning of day 3 of his hospitalization the delirium has resolved and the patient has a normal mental status. He is transferred to an inpatient psychiatric facility.
- Physostigmine can be used as an antidote for what type of poisoning?
- What are potential complications associated with the administration of physostigmine?
A multitude of drugs and plants block muscarinic receptors. Drugs include tricyclic antidepressants, antihistamines, and various neuroleptics. Unlike these other medicinal agents that possess other receptor effects in addition to muscarinic blockade, atropine is a purely antimuscarinic drug. A number of plants, such as Datura stramonium (Jimsonweed) contain antimuscarinic components.
As an acetylcholinesterase inhibitor, physostigmine inhibits the breakdown of acetylcholine at cholinergic synapses. More acetylcholine therefore remains present that can now compete for the muscarinic acetylcholine receptor that may be blocked by various antimuscarinic agents. Physostigmine is a tertiary amine allowing it to penetrate the blood brain barrier and antagonize central as well as peripheral muscarinic receptors. The acetylcholinesterase inhibition by physostigmine is reversible and the drug is metabolized rapidly, so the antagonism of muscarinic receptors is only temporary.
Some potential complications of physostigmine administration can be predicted based on its mechanism of action. Signs of cholinergic excess including SLUDGEing (Salivation, Lacrimation, Urination, Defecation, Gastrointestinal distress, and Emesis) would all be expected as a result of physostigmine excess. Bradycardia may occur as a result of an increased parasympathetic tone. Additionally, convulsions may occur as a result of central cholinergic excess. The etiology of the convulsions can be difficult to determine when physostigmine has been administered, as many antimuscarinic agents themselves may induce convulsions. The most significant complication associated with physostigmine administration has been the rare occurrence of asystole. It seems clear from the literature that certain patients are at risk of asystole from physostigmine administration. In each of the 4 reported cases of asystole, physostigmine was administered therapeutically to patients severely poisoned with tricyclic antidepressants. An animal study supports the potential risk of physostigmine administration in the setting of severe tricyclic antidepressant poisoning.
Potential uses for physostigmine include both diagnostic and therapeutic purposes. Therefore, patients in whom the use of physostigmine may be considered will have a physical examination consistent with an antimuscarinic agent. Antagonism of muscarinic receptors may lead to an antimuscarinic toxidrome characterized peripherally by tachycardia, mild hyperthermia, mydriasis, diminished bowel sounds, dry skin, urinary retention, and picking behavior. Delirium is the primary central manifestation of antimuscarinic poisoning. The combination of delirium and dry mouth often leads to incomprehensible, mumbling speech. Although some patients may exhibit all of the signs of antimuscarinic blockade there, the presentation can be variable. The delirium itself often precludes the patient from explaining what agent he was exposed to.
Physostigmine may be used diagnostically in the evaluation of a patient with delirium of unclear etiology. In such a setting, as in the case described above, the patient should have a physical examination that suggests antimuscarinic poisoning. Reversal of delirium after physostigmine administration may help confirm an antimuscarinic etiology and prevent the need for further diagnostic evaluations, including brain imaging and lumbar puncture. To date, only one small series details strictly diagnostic use of physostigmine. In this series, physostigmine administration was without significant complication. Physostigmine administration has also been reported to reverse altered mental status stemming from drugs that do not have antimuscarinic properties. Therefore, reversal of altered mental status after physostigmine administration unfortunately does not necessarily confirm an antimuscarinic etiology.
A fairly large body of literature exists detailing the therapeutic use of physostigmine. Physostigmine has been used for the purpose of anesthesia reversal, hallucination decrease, agitation control, and even dysrhythmia treatment following antimuscarinicpoisoning. Such therapeutic use has occasionally been associated with convulsions and other signs and symptoms of cholinergic excess. As mentioned already, asystole has been reported in the setting of severe tricyclic antidepressant overdose. In each of the four cases reported, the patients were manifesting classical signs of tricyclic antidepressant poisoning including convulsions and QRS prolongation on their electrocardiogram. As a result of these cases and some animal literature that supports the danger of physostigmine use in the setting of tricyclic antidepressant poisoning, the use of physostigmine is contraindicated in anyone known or suspected to be acutely poisoned with these agents. As with the use of any antidote, one must always be confident that the benefit of its use outweighs its potential harm.
Discussion of case questions
- Physostigmine can be used as an antidote in what type of poisoning?
Patients suspected of, or known to be poisoned by various drugs or plants with antimuscarinic properties may be considered for physostigmine administration. Such patients may manifest signs of the antimuscarinic toxidrome resulting from muscarinic receptor blockade. This toxidrome is characterized peripherally by tachycardia, mild hyperthermia, mydriasis, diminished bowel sounds, dry skin, urinary retention, and picking behavior. Delirium is the primary central manifestation of antimuscarinic poisoning. The combination of delirium and dry mouth often manifest as incomprehensible, mumbling speech. As with the use of any antidote one must always consider the risk to benefit ratio of its administration.
- What are potential complications associated with the administration of physostigmine?
The most feared complication of physostigmine administration is asystole. This has been reported in a total of four patients who were severely poisoned with tricyclic antidepressants as manifested by convulsions and QRS prolongation. For this reason the administration of physostigmine to patients acutely poisoned with tricyclic antidepressants is contraindicated. Physostigmine may also lead to signs of cholinergic excess including SLUDGEing (salivation, lacrimation, urination, defecation, gastrointestinal distress, and emesis). Bradycardia may occur as a result of increased parasympathetic tone. Lastly, convulsions may occur but may be difficult to attribute solely to physostigmine as many drugs with antimuscarinicproperties that physostigmine is used to reverse, may also be associated with convulsions.