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The
Official Newsletter of the
Volume
2, Number 3.
Fall, 2004
Physostigmine
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Introduction
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.
Case presentation
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) are
normal. 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.
Questions:
1.
Physostigmine can be used as an antidote for what type of poisoning?
2.
What are potential complications associated with the administration of
physostigmine?
Epidemiology
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.
Pathophysiology
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.
Clinical presentation
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.
Diagnosis
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.
Treatment
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 antimuscarinic
poisoning. 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
1.
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.
2.
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 antimuscarinic
properties that physostigmine is used to reverse, may
also be associated with convulsions.
Consultation assistance
Consultation
with a specialist in poison information or with a medical toxicologist can be
obtained free of charge by calling the California Poison Control System at
1-800-411-8080.
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