1. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Anticholinergic Poisoning Andrew Dawson, Newcastle Mater Hospital Robert Hoffman, New York Poison Centre

2. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Belladonna Atropa belladonna (Solanaceae)

3. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Kinetics  Rapidly absorbed –Prolonged absorption in overdose  Large volume of distribution and rapid distribution  Low hepatic clearance

4. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Dynamics  5 muscarinic subtypes:  Different tissue distributions with some overlap –M1 receptors: CNS –M2 receptors:CNS and heart –M3 receptors: Salivary glands –M4 receptors: Brain and lungs  Different affinity at different receptors

5. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

6.  Central Anticholinergic Syndrome –Delirium (Hyperactive or Hypoactive) –Seizures  Peripheral Anticholinergic Syndrome –thirst, dry mouth, dilated pupils, tachycardia, flushed face, slowed gastric emptying and decreased bowel sounds, dry skin, hyperthermia, urinary retention.

7. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

8. Anticholinergic Delirium  Acute confusional state  Blockade of cholinergic muscarinic receptors –Pure anticholinergic drugs –Many psychiatric drugs –Plants  40-50 admissions per annum –Delirium doubles mean duration of stay to 56 hours –Increased levels of staffing

9. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Treatment Options  Reassurance  Physical Containment  Sedation - benzodiazepines  Physostigmine  Close observation  Risk of medical complications

10. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Efik People

11. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Physostigm a venosum

12. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital 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

13. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital “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

14. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Hydrolysis of Acetylcholine CH 3 C O OCH 2 CH 2 NCH 3 CH 3 CH 3 + Cholinesterase Serine Anionic site Esteratic site

15. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital ? Anticholinesterases

16. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital 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

17. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital  #3: “extreme drunkenness”; laughing, delirious, unable to speak coherently, flushed, dilated pupils, temp 38.7 o C, pulse 70/min, ? movement disorder.  #4: Unable to stand, flushed, elevated temperature, tachypnea, very dilated pupils, dry mouth, coma alternating with agitation.

18. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital  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

19. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital  2:30 PM: –#4 was conscious, sitting up, able to answer questions. Pupils still dilated –#3 unchanged  Next day –#4 Normal –#3 Still poisoned

20. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Comparison of Physo and BZs  Retrospective review of 52 patients with anticholinergic symptoms  Physostigmine –Controlled agitation: 96% –Reversed delirium: 87%  Benzodiazepines –Controlled agitation:24% –Reversed delirium:9%

21. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital  Physostigmine –Lower incidence of complications l 7% vs 46% –Shorter recovery time l 12 vs 24 hours  No difference in side effects –Burns et al: Ann Emerg Med 2000;35:374-381

22. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Pal in 1900 Reverses Curare

23. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Tacrine in anticholinergic delirium  Unblinded Study:  26 patients –15 Retrospective chart review clinical toxicology database –11 Prospective pilot study safety & dose ranging l Safety primary outcome l Efficacy secondary outcome

24. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Defining Success / Response  Documented clinical resolution of symptoms  Patient as being described as being lucid  Shift in 1 level of care

25. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Response Duration  The Mean duration of 1st response