Transcript Physostigmine

Physostigmine
The Pendulum Swings
Robert S. Hoffman, MD
Efik People
Physostigma
venosum
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
“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
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
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
Physostigmine or Eserine
First Isolated in 1864 by Jobst and
Hesse
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
• #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.
• 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
• 2:30 PM:
 #4 was conscious, sitting up, able to
answer questions. Pupils still dilated
 #3 unchanged
• Next day
 #4 Normal
 #3 Still poisoned
Pal in 1900
Reverses Curare
Pharmacology
Hydrolysis of Acetylcholine
O
CH3 C
CH3
O
CH2 CH2
CH3
N CH3
+
Serine
Esteratic
site
Anionic
site
Cholinesterase
OH
CH3 C
CH3
O
CH2 CH2
CH3
N CH3
+
O
CH3
C
CH3
N+ CH3
O CH2 CH2
CH3
O
CH3
N
C
O
H
N
N
CH3
CH3
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
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
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.
Modern Antidotal Therapy
Antidote vs. Analeptic
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
Analeptics in Overdose
Management
•
•
•
•
•
•
Pentalenetetazol
Nikethamide
Amphetamines
Caffeine
Strychnine
Largely abandoned ~ 1960
 Clemmesen
Post Operative Effects
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
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
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
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)
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
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
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
Human Volunteers
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
Overdose Management
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
Physostigmine for TCAs
•
•
•
•
4 patients
Reduction in heart rate
Arousal within 20 minutes
No adverse effects
 Slovis: Clin Toxicol 1971;4:451
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
Physostigmine for TCAs
• 2 patients
• #1: Treated twice, 4 hours apart
• #2: Received multiple doses over 8
hours.
 Snyder: JAMA 1974;230:1433
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
More Tricyclic Antidepressants
• 254 with TCAs
• Physostigmine appeared to:
 Terminate seizures
 Improve conduction
 Rumack 1975: 707 anticholinergic patients
 See Chris Linden on ACMTnet
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
Other Anticholinergic Agents
• Other agents became prominent in
overdose
 Plants
 Antihistamines
 Phenothiazines
• Rumack: Pediatrics 1973;52:449
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”
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
Nattel Conclusions
• The effects of physostigmine in nonanticholingeric 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….
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
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)
Conclusion
• “…the diagnostic value of
physostigmine was considerable, but
the therapeutic benefit was limited.”
 Nilsson: Ann Clin Research 1982;14:165
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
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.
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
Dead But Not Forgotten
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
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
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
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
Total n=373
Physostigmine given in 77
Is Physostigmine An
Antidote to Everything?
Or
Non-Specific Analeptic?
Arousal Is Only Beneficial If It
Improves Outcome!
•
•
•
•
•
•
Pentalenetetazol
Nikethamide
Caffeine
Strychnine
Amphetamine
Physostigmine?
Unfortunately Only One
Outcome Study
Comparison of Physo and BZs
• Retrospective review of 52 patients with
anticholingeric symptoms
• Physostigmine
 Controlled agitation:
 Reversed delirium:
96%
87%
• Benzodiazepines
 Controlled agitation:
 Reversed delirium:
24%
9%
• 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
Personal Opinion
Guided By The Literature
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