Agency for Toxic Substances and Disease Registry Case Studies in Environmental Medicine Cholinesterase Inhibitors: Including Pesticides and Chemical Warfare Nerve Agents Course: WB1102 CE Original Date: October 17, 2007 CE Expiration Date: October 17, 2010 Table of Contents Table of Contents..................................................................................................... 1 Table of Figures ....................................................................................................... 2 Table of Figures ....................................................................................................... 2 How to Use This Course ............................................................................................ 5 Learning Objectives.................................................................................................. 6 Initial Check.......................................................................................................... 10 Part 1: Community Preparedness for Mass Casualty Events Involving Cholinesterase Inhibitors.............................................................................................................. 14 Part 2: What are cholinesterase inhibitors? ................................................................ 18 Part 3: What types of pathology do cholinesterase inhibitors cause?.............................. 23 Part 4: The Cholinergic Toxidrome............................................................................ 25 Section 1: What is the Cholinergic Toxidrome?........................................................ 25 Section 2: Nicotinic Acetylcholine Receptors ........................................................... 28 Section 3: Muscarinic Acetylcholine Receptors......................................................... 32 Section 4: Clinical Findings in Cholinesterase Inhibitor Toxicity Are Due to a Mixture of Nicotinic and Muscarinic Effects ............................................................................ 37 Section 5: Signs and Symptoms by Route of Exposure and Chemical Structure of the Involved Cholinesterase Inhibitor (Optional Reading) ............................................... 43 Section 6: Effects on Routine Laboratory Tests........................................................ 46 Section 7: Differential Diagnosis of the Cholinergic Toxidrome................................... 48 Section 8: Signs and Symptoms: Differences in Pediatric Cases................................. 52 Section 9: Importance of the Exposure History ....................................................... 54 Section 10: Laboratory Assessment of the Cholinergic Toxidrome .............................. 58 Red Blood Cell (RBC) and Serum Cholinesterase Levels......................................... 58 Direct Measurement of Cholinesterase Inhibitors and Their Metabolic Byproducts...... 62 Section 11: Management of the Cholinergic Toxidrome ............................................ 64 Management Strategy 1: Prevention of Secondary Exposure ..................................... 65 Management Strategy 2: Supportive Care .............................................................. 69 Management Strategy 3: Medications .................................................................... 70 Medications: Atropine ...................................................................................... 71 Medications: 2-PAM (2-Pyridine Aldoxime Methylchloride) (Pralidoxime) .................. 83 Medications: Diazepam .................................................................................... 95 Antidote Stocking (Optional Reading) ................................................................. 97 Section 12: Public Health and Medico-Legal Issues .................................................102 Part 5: The Intermediate Syndrome.........................................................................104 Part 6: Organophosphate-Induced Delayed Neuropathy (OPIDN) .................................108 Part 7: Organophosphorus Ester-Induced Chronic Neurotoxicity (OPICN) ......................111 Part 8: Other Issues Related to Cholinesterase Inhibitor Exposure................................113 Posttest Instructions..............................................................................................116 References...........................................................................................................129 Answers to Progress Check Questions ......................................................................140 Agency for Toxic Substances and Disease Registry Case Studies in Environmental Medicine Cholinesterase Inhibitors: Including Pesticides & Chemical Warfare Nerve Agents Table of Figures Figure 1. Breakdown of acetylcholine. ....................................................................... 18 Figure 2. Partially electropositive phosphorus is attracted to partially electronegative serine. ........................................................................................................................... 19 Figure 3. Transition state showing which bonds break and which ones form.................... 19 Figure 4. Cholinesterase inhibitor attached to acetylcholinesterase preventing the attachment of acetylcholine..................................................................................... 19 Figure 5. Summary diagram showing where nicotinic and muscarinic receptors are found. Refer back to this when reading the following sections. ............................................... 26 Figure 6. The nicotinic receptor. Figure modified with permission from: Guyton AC, Hall JE: Textbook of Medical Physiology (2006) Elsevier Saunders, Philadelphia. P.87. Used with permission. ........................................................................................................... 29 Figure 7. The muscarinic (G-protein) receptor. Modified with permission from: Guyton AC, Hall JE: Textbook of Medical Physiology (2006) Elsevier Saunders, Philadelphia. p. 561. Used with permission. ............................................................................................ 33 Figure 8. Frequency of Signs and Symptoms in Cholinesterase Inhibitor Toxicity. ............ 40 Figure 9. Pediatric signs and symptoms. Data from: Sofer S, Tal A, Shahak E. Carbamate and organophosphate poisoning in early childhood. Pediatric Emergency Care. 1989; 5:222- 225...................................................................................................................... 52 Figure 10. Military MARK I Kit containing atropine and 2-PAM autoinjectors. Source: U.S. Army Soldier and Biological Chemical Command (SBCCOM). ........................................ 74 Figure 11. X-ray showing autoinjector effectiveness. The rapid absorption of antidote following automatic injection is enhanced by the degree of tissue dispersion achieved by the autoinjector. The X-ray shows autoinjector doses (on left) compared to standard syringe IM doses (on right). The autoinjector medication is obviously more efficiently diffused into surrounding muscle due to the force with which it is expelled from the injector (as seen in inset photo.) Source: U.S. Army, SBCCOM. (Note: the correct way to view an X-ray is as if the patient was facing you. Thus, the patient’s left side is shown on the right.)............... 75 Figure 13. How the positively charged nitrogen in the acetylcholine molecule is attracted to the ionic site on acetylcholinesterase, and hydrolysis is catalyzed at the esteric site to form choline and acetic acid............................................................................................ 84 Figure 14. Partially electropositive phosphorus is attracted to partially electronegative serine................................................................................................................... 85 Figure 15. Transition state showing which bonds break and which ones form. ................. 85 Figure 16. Cholinesterase inhibitor attached to acetylcholinesterase preventing the attachment of acetylcholine..................................................................................... 85 Figure 17. Cholinesterase is blocked, but it can: ......................................................... 86 Figure 18. The “aged” bond ..................................................................................... 86 Figure 19. How 2-PAM works. .................................................................................. 87 Figure 20. Partially electropositive nitrogen on 2-PAM is attracted to electronegative anionic site on cholinesterase. ............................................................................................ 87 Figure 21. Regenerated cholinesterase. ..................................................................... 87 Page 2 of 153 Agency for Toxic Substances and Disease Registry Case Studies in Environmental Medicine Cholinesterase Inhibitors: Including Pesticides & Chemical Warfare Nerve Agents Key Concepts • Cholinesterase inhibitors are a class of compounds that includes chemical warfare nerve agents and certain insecticides. • Fatalities occur mainly due to effects on respiration due depression of respiratory drive, paralysis of muscles of respiration, bronchoconstriction, and airway obstruction from profuse respiratory tract secretions. • Treatment includes the use of atropine, 2-PAM, diazepam, and aggressive supportive care. About This and This educational case