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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

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Physostigmine

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  1. Physostigmine The Pendulum Swings Robert S. Hoffman, MD

  2. Efik People

  3. Physostigma venosum

  4. 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

  5. “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

  6. 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

  7. 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

  8. Physostigmine or EserineFirst Isolated in 1864 by Jobst and Hesse

  9. 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

  10. #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.

  11. 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

  12. 2:30 PM: • #4 was conscious, sitting up, able to answer questions. Pupils still dilated • #3 unchanged • Next day • #4 Normal • #3 Still poisoned

  13. Pal in 1900 Reverses Curare

  14. Pharmacology

  15. Serine Esteratic site Anionic site Cholinesterase Hydrolysis of Acetylcholine O C H C H 3 3 C H C O C H C H N C H 3 2 2 3 +

  16. 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

  17. 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

  18. 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.

  19. Modern Antidotal TherapyAntidote vs. Analeptic

  20. 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

  21. Analeptics in Overdose Management • Pentalenetetazol • Nikethamide • Amphetamines • Caffeine • Strychnine • Largely abandoned ~ 1960 • Clemmesen

  22. Post Operative Effects

  23. 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

  24. 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

  25. 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

  26. 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)

  27. 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

  28. 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

  29. 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

  30. Human Volunteers

  31. 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

  32. Overdose Management

  33. 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

  34. Physostigmine for TCAs • 4 patients • Reduction in heart rate • Arousal within 20 minutes • No adverse effects • Slovis: Clin Toxicol 1971;4:451

  35. 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

  36. Physostigmine for TCAs • 2 patients • #1: Treated twice, 4 hours apart • #2: Received multiple doses over 8 hours. • Snyder: JAMA 1974;230:1433

  37. 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

  38. More Tricyclic Antidepressants • 254 with TCAs • Physostigmine appeared to: • Terminate seizures • Improve conduction • Rumack 1975: 707 anticholinergic patients • See Chris Linden on ACMTnet

  39. 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

  40. Other Anticholinergic Agents • Other agents became prominent in overdose • Plants • Antihistamines • Phenothiazines • Rumack: Pediatrics 1973;52:449

  41. 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”

  42. 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

  43. 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….

  44. 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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