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Physostigmine
The Pendulum Swings
Robert S. Hoffman, MD
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Efik People
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Physostigma venosum
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Efik Law
• Trial by ordeal
• Deadly esere Administration of the Calabar bean
• First observed by WF Daniell in 1840
• Later described by Freeman 1846 in a Communication to the Ethnological Society of Edinburgh
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“A suspected person is given 8 beans ground and added to water as a drink. If he is guilty, his mouth shakes and mucus comes from his nose. His innocence is proved if he lifts his right hand and then regurgitates.
If the poison continues to affect the suspect after he has established his innocence, he is given a concoction of excrement mixed in water which has been used to wash the external genitalia of a female.”
Simmons 1952
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Early Clinical Effects
• Christison and Frasier (c. 1863) Bradycardia and weak pulse Muscular paralysis Excitation of the secretory system Pupillary constriction
Cardiac and pupillary effects antagonized by atropine
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Argyll Roberston 1863
• Pupillary constriction is caused by contraction of the circular fibers of the iris
• Subsequently experimental use for: Reversing atropine induced pupillary
dilation Photophobia in patients with retinitis Glaucoma Myasthenia gravis
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Physostigmine or EserineFirst Isolated in 1864 by Jobst and
Hesse
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First Use As An Antidote
• Kleinwächter 1864 4 prisoners drank atropine solution thinking
it was liquor 9AM estimated atropine dose 64 mg total One patient was asymptomatic (spat it out) Another had dilated pupils, with a normal
pulse and temperature
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• #3: “extreme drunkenness”; laughing, delirious, unable to speak coherently, flushed, dilated pupils, temp 38.7 oC, pulse 70/min, ? movement disorder.
• #4: Unable to stand, flushed, elevated temperature, tachypnea, very dilated pupils, dry mouth, coma alternating with agitation.
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• Tried ipecac, coffee, tannic acid and cinnamon
• Unable to give beer with tartar emetic
• Both patients deteriorated
• Gave Calabar extract (about 1 mg physostigmine) to #4, keep #3 as a control
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• 2:30 PM: #4 was conscious, sitting up, able to
answer questions. Pupils still dilated #3 unchanged
• Next day #4 Normal #3 Still poisoned
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Pal in 1900 Reverses Curare
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Pharmacology
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Hydrolysis of Acetylcholine
CH3 C
O
O CH2 CH2 N CH3
CH3CH3
+
Cholinesterase
SerineAnionic
siteEsteratic
site
CH3 C
OH
O+
CH2 CH2 N CH3
CH3CH3
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N C O
OCH3
H
N
N
CH3
CH3
CH3 C O
O
CH2 CH2 N+
CH3
CH3
CH3
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Pharmacology
• Leaving group is released
• Carbamoylated enzyme results
• Hydrolyis of cholinesterase Acetylated: 150 msec Carbamoylated: 15-30 minutes
• I50 is very weak: 2.3 x 10-7 molar 1 x 10-11 for many organophosphates
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Pharmacokinetics
• In human volunteers, the following data were observed Vd: 2.4 L/kg T1/2: 16.4 minute T1/2 of plasma cholinesterase inhibition is
longer: 84 minutes
• Large individual variations were noted• Hysteresis
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Analeptic Effects
• Low dose: EEG develops a high frequency, low amplitude electrical pattern consistent with an alert state, behavior is not altered
• Dose-response progressive increase in EEG activity and behavior, leading to seizures.
• Bokums JA: Effects of physostigmine on electrical activity of the cat brain: Pharmacology 1968:1:98-110.
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Modern Antidotal TherapyAntidote vs. Analeptic
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Governing Principles
• Clinicians do not like delirious or unconscious patients
• Somehow these conditions are equated with undesirable outcomes
• Critical flaw: Arousal and alertness do not necessarily equal improvement
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Analeptics in Overdose Management
• Pentalenetetazol
• Nikethamide
• Amphetamines
• Caffeine
• Strychnine
• Largely abandoned ~ 1960 Clemmesen
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Post Operative Effects
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Scopolamine (Twilight Sleep) During Anesthesia
• Retrospective: 185 patients given physostigmine after surgery
• 177 “prompt and dramatic” response• 6 failures; all responded to a second
dose• Half had increased salivation; 1
bradycardia• Holzgrafe: Anesth Analg 1973;52:921
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Scopolamine During Delivery
• 15 patients
• All normalized in 2-5 minutes
• 2 developed apprehension
• 3 relapsed at about 2 hours• Smiler: Am J Obstet Gynecol 1973;116:326
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Halothane
• 230 adult elective surgery patients
• 2 mg physostigmine given at then end of the case
• “significant” reversal of postoperative somnolence
• Hill: Can Anaesth Soc J: 1977;24:707
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Physostigmine for Ketamine
• Supporting Toros-Matos: Anesth Analg 1980;59:764 (n=7) Hamilton-Davies: Anaesthesia 1995;50:458 (n=28)
• No benefit Engelhardt: Anesthesist 1994;43:S76 (n=12)
• Worse Drummond: Can Anaesth Soc J 1979;26:288
(n=111)
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Proprofol
• Randomized double blind study
• Sample: 40 females
• 2mg of physostigmine or saline 5 minutes before propofol
• Outcome: dose of propofol required to lose the ability to grasp a 20cc syringe
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Results
• Dose of propofol Physostigmine: 2.4 mg/kg Saline: 2.0 mg/kg P=0.014
• Fassoulaki A: Can J Anesth 1997;44:1148
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Reversal of Propofol
• Measured by bispectral index (n=17)
• 9/11 subjects physostigmine rapidly reversed unconsciousness
• 6 more given scopolamine had no response
• Meuret P: Anesthesiology 2000;93:708
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Human Volunteers
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Scopolamine Volunteers
• 33 subjects (9 were control)
• Scopolamine followed by physostigmine at various times
• Mental ability tested using a standard battery
• Crowell: Clin Pharm Ther 1967;8:409
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Overdose Management
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Tricyclic Antidepressants
• Shortly after marketing, TCAs became one of the leading causes of fatality
• Complex drugs Anticholinergic Quinidine-like sodium channel blockade Alpha adrenergic antagonists GABAA antagonists
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Physostigmine for TCAs
• 4 patients
• Reduction in heart rate
• Arousal within 20 minutes
• No adverse effects
Slovis: Clin Toxicol 1971;4:451
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Physostigmine for TCAs
• 2 patients
• #1: Treated 26 times in 13 hours Discharged 4 days later
• #2: Treated twice Spent 3 days in ICU
• No adverse effects Burks: JAMA 1974;230:1405
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Physostigmine for TCAs
• 2 patients
• #1: Treated twice, 4 hours apart
• #2: Received multiple doses over 8 hours.
Snyder: JAMA 1974;230:1433
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Physostigmine for TCAs
• Single patient: Obtunded, QRS ~120 msec• Physostigmine 2mg x3 doses with minimal
improvement• Later QRS increased to 160 msec, ? V-tach• Lidocaine was minimally efficacious• 22 mg physostigmine over 48 hours• Retreatment at 6 days produced a seizure
Tobis: JAMA 1976;235:1474
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More Tricyclic Antidepressants
• 254 with TCAs
• Physostigmine appeared to: Terminate seizures Improve conduction
Rumack 1975: 707 anticholinergic patients See Chris Linden on ACMTnet
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Physostigmine Worked
• Improved mental status Reversal of anticholinergic effect “Non-specific analeptic effect
• Treated seizures Reversal of anticholinergic effect
• Treated conduction abnormalities Bradycardia improved use dependent
blockade of sodium channels
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Other Anticholinergic Agents
• Other agents became prominent in overdose Plants Antihistamines Phenothiazines
• Rumack: Pediatrics 1973;52:449
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Net Result
• Since many cases of obtundation or delirium were related to anticholinergics
AND• Physostigmine appeared “safe”
is was routinely given as a “diagnostic and therapeutic tool”
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Drug Overdose
• 12 patients
• double-blind, placebo-crossover
• Evaluated level of consciousness, vital signs, pupil size
• Response in 3/9 non-anticholinergics and 2/3 anticholinergics Nattel: Clin Pharm Ther 1979;25:96
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Nattel Conclusions
• The effects of physostigmine in non-anticholingeric overdose appear to be due to a nonspecific action on the central nervous system
• Physostigmine may also be of benefit in the differential diagnosis of coma.
• It’s routine use is not recommended….
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More Mixed Overdose
• 83 unconscious or severely disoriented patients
• 2 mg doses repeated until maximal effect
• Followed vital signs and level of consciousness Nilsson: Ann Clin Research 1982;14:165
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Response Rates
• Anticholinergics (n=35): 91%
• Benzodiazepines (n=12): 67%
• Non-anticholinergic (n=22): 32%
• Unclassified (n=14): 50%
• Relapses: 21/32 in anticholinergic group; less in other groups
• Adverse effects; PVC (1), Seizure (1)
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Conclusion
• “…the diagnostic value of physostigmine was considerable, but the therapeutic benefit was limited.”
Nilsson: Ann Clin Research 1982;14:165
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Tricyclic Deaths
• 2 patients developed asystole• Both complex cases
Both given atropine prior to asystole Hypothesized “low-dose” atropine effect One had coingestion of propranol
• Pentel: Ann Emerg Med 1980;9:588
Tong: Drug Intel Clin Pharm 1976;10:711 Shannon: Peds Emerg Care 1998;14:224
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Net Result
• Over time, physostigmine was abandoned for TCAs
• Because of the fear from these 4 cases, routine use of physostigmine was almost completely abandoned.
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Datura Poisoning
• 73 cases in one series
• 23 reversed with physostigmine
• No adverse effects Klein-Schwartz: Am J Dis Child 1984:138:737
• Others advise against physostigmine citing risk:benefit analysis Rodgers: Vet Hum Toxicol 1993;35:32
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Dead But Not Forgotten
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Heroin Overdose
• 10 overdoses
• Randomized to physostigmine 0.04 mg/kg or naloxone 3mcg/kg
• All awoke within 10 minutes; no differences in vital signs
• No withdrawal with physostigmine Rupreht: Clin Toxicol 1983-84;21:387
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Benzodiazepines
• 8 human volunteers
• Sleep induced by diazepam
• Double-blind dosing of physostigmine
• All patients awoke by 12 minutes
• No effect of placebo at 16 minutes
• 6/8 had side effects Avant: Ann Intern Med 1979;91:53
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Benzodiazepines
• 12 volunteers given midazolam
• Randomized to placebo, flumazenil, or physostigmine in crossover design
• EEG and awakening studied
• Effect of placebo; 25 minutes
• Flum > Physo; 6 vs 15 Ebert: Clin Pharm Ther 2000;67:538
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Analeptic vs Antagonist
• GABA decreases acetylcholine release Moor: Eur J Pharmacol 1998;359:119 Supavilai: Life Sci 1985;36:417
• Flumazenil increases acetylcholine release Imperato: Brain Research 1994;647:167
• Physostigmine inhibits binding at the benzodiazepine and opioid receptors Speeg: J Neurochemistry 1980;34:856
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Total n=373Physostigmine given in 77
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Is Physostigmine An
Antidote to Everything?
Or
Non-Specific Analeptic?
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Arousal Is Only Beneficial If It Improves Outcome!
• Pentalenetetazol
• Nikethamide
• Caffeine
• Strychnine
• Amphetamine
• Physostigmine?
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Unfortunately Only One Outcome Study
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Comparison of Physo and BZs
• Retrospective review of 52 patients with anticholingeric symptoms
• Physostigmine Controlled agitation: 96% Reversed delirium: 87%
• Benzodiazepines Controlled agitation: 24% Reversed delirium: 9%
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• Physostigmine Lower incidence of complications
• 7% vs 46%
Shorter recovery time• 12 vs 24 hours
• No difference in side effects
Burns et al: Ann Emerg Med 2000;35:374-381
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Personal Opinion
Guided By The Literature
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Physostigmine Should Be Used
• When indicated Clinically anticholinergic Need for chemical or physical restraints Need for other diagnostic testing
• When safe Normal QRS complex duration ? Asthma
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