1. NERVE AGENTS

2. DEFINITION  A substance that causes biological effects by inhibiting acetylcholinesterase  Acetylcholine accumulates  Effects are due to excess acetylcholine

3. EXAMPLES  Carbamates  Physostigmine (Antilirium)  Neostigmine (Prostigmine)  Pyridostigmine (Mestinon)  Sevin (insecticide)  Organophosphates  Malathion  Diazinon  “Nerve Agents”

4. NERVE AGENTS  GA (Tabun)  GB (Sarin)  GD (Soman)  GF  VX

5. GB CH 3 P O CH O F CH 3

6. VX P S CH 2 CH 2 N O CH 3 CH 3 CH 2 O CH(CH 3 ) 2

7. PHYSICAL PROPERTIES  Clear, colorless liquids (when fresh), not “nerve gas”  Tasteless, most are odorless  Freeze/melt <0º C  Boil >150º C  Volatility GB>GD>GA>GF>>VX  Penetrate skin, clothing

8. TOXICITY LCt 50 LD 50 mg-min/m 3 mg/70kg GA4001,000 GB1001,700 GD7050 GF5030 VX1010

9. LD50 of VX

10. PHYSIOLOGY: NORMAL  Electrical impulse goes down nerve  Impulse causes release of neurotransmitter, acetylcholine (Ach)  ACh stimulates receptor site on organ  Causes organ to act  ACh is destroyed by AChE (Acetylcholinesterase)  No more organ activity

11. NERVE TRANSMISSION: NERVE TO NERVE

12. NERVE TRANSMISSION: NERVE TO SKELETAL MUSCLE

13. NERVE TRANSMISSION: NERVE TO SMOOTH MUSCLE

14. NERVE TRANSMISSION: NERVE TO EXOCRINE GLAND

15. IMPULSE TERMINATION: THE ROLE OF ACHE

16. PHYSIOLOGY: NERVE AGENT  Enzyme (AChE) is inhibited  Does not destroy ACh  Excess ACh continues to stimulate organ  Organ overstimulation

17. EXPOSURE TO NERVE AGENT

18. EFFECTS ON STRIATED (SKELETAL) MUSCLE

19. EFFECTS ON SMOOTH AND CARDIAC MUSCLE

20. EFFECTS ON EXOCRINE GLANDS

21. TWO MAJOR TYPES OF CHOLINERGIC RECEPTORS  Muscarinic  Smooth muscles  Exocrine glands  Cranial nerves (vagus)  Nicotinic  Skeletal muscles  Pre-ganglionic nerves  Both  CNS

22. CHOLINERGIC MUSCARINIC EFFECTS  Muscarinic  Smooth muscles  Airways - constrict  GI tract - constrict  Pupils - constrict  Glands  Eyes, nose, mouth, sweat, airways, GI  Heart, bradycardia (vagal)

23. CHOLINERGIC NICOTINIC EFFECTS  Skeletal muscles  Fasciculations, twitching, fatigue, flaccid paralysis  Pre-ganglionic  Tachycardia, hypertension

24. ACh at RECEPTORS ACh Nicotinic Muscarinic Preganglionic synapses in ANS Skeletal muscle Synapses in CNS Smooth muscle Exocrine glands

25. HEART RATE VARIABLE  Muscarinic (vagal) decreases ( )  Nicotinic (ganglionic) increases ( )  Hypoxia: decrease oxygen ( )  May be high, low, normal ( )

26. CENTRAL NERVOUS SYSTEM (CNS)  Acute, large exposure to nerve agent  Loss of consciousness  Seizures  Apnea  Death

27. CNS  Acute, small exposure to nerve agent  Minor CNS effects  Slowness in thinking and decision making  Sleep disturbances  Poor concentration  Emotional problems  Other minor problems

28. CNS  Minor CNS effects  May last for 3 to 6 weeks  May follow any exposure  Not always present  Very slight, subtle

29. VAPOR  Small exposure  Eyes: Miosis; injection; dim, blurred vision; pain; maybe nausea, vomiting  Nose: Rhinorrhea  Mouth: Salivation  Airways: Shortness of breath

30. VAPOR - RESPIRATORY TRACT  Small exposure  Tight chest  Moderate exposure  Severe breathing difficulty  Gasping, irregular breathing  Compounded by excessive secretions

31. VAPOR - GASTROINTESTINAL  Exposure to a large but not lethal concentration may cause:  Nausea, vomiting  Pain in abdomen  Diarrhea, involuntary defecation or urination

32. VAPOR  Large exposure  Previously listed effects plus...  Loss of consciousness  Seizures  Apnea  Flaccid paralysis  Death

33. VAPOR  Onset of effects: seconds to minutes  After removal from vapor  Effects do not worsen  May improve  No late-onset effects

34. LIQUID ON SKIN  Small droplet: local effects  Sweating, fasciculations  Medium droplet: systemic effects  GI  Large droplet: pulmonary and CNS  Respiratory distress, apnea, death  Loss of consciousness, seizures, apnea, flaccid paralysis, death

35. LIQUID ON SKIN  Onset of effects  Small, medium drop  As long as 18 hours  Large, lethal drop  Usually <30 minutes

36. LIQUID ON SKIN  Effects may occur despite initial decontamination  Effects may worsen

37. MIOSIS  Almost always after vapor  After liquid on skin:  Small: no  Moderate: maybe  Severe: yes

38. PHOTO OF NORMAL PUPIL RESPONSE

39. PHOTO OF PINPOINT PUPIL

40. NERVE AGENT EFFECTS - EYES 3 6 13 20 41 62 Days after exposure

41. MANAGEMENT  ABCs  Drugs (nerve agent antidotes)  Decontamination  Supportive  Anticonvulsant therapy  Not necessarily in this order!

42. MANAGEMENT  MOST IMPORTANT  Protect self  Protective gear  Decontaminate casualty  Protect medical facility  Decontaminate casualty

43. SKIN DECONTAMINATION  Early is best, within 1 to 2 minutes  Little benefit after 30 minutes  Physical removal is best  Forceful flush with water  Stick, dirt, cloth, M291  Solutions (hypochlorite, etc.)  Detoxify after many minutes

44. VENTILATION  Possibly less need after pyridostigmine  None forward of Battalion Aid Station  Very high airway resistance until atropine is given

45. ANTIDOTES  Too much acetylcholine  Block excess acetylcholine  Enzyme inhibited  Reactivate enzyme

46. ATROPINE  A cholinergic blocking drug  An anticholinergic  Blocks excess acetylcholine  Clinical effects at muscarinic sites  Dries secretions  Reduces smooth muscle constriction

47. ATROPINE at RECEPTORS

48. ACH AND ATROPINE at RECEPTORS

49. ATROPINE  Side effects in unexposed  Starting dose 2 mg or 6 mg  More, 2 mg every 5 to 10 minutes  Until  Secretions drying  Ventilation improved  Usual dose: (severe casualty) 15 to 20 mg  1000s of mgs in insecticide

50. ATROPINE  Not for  Skeletal muscle effects  Miosis, unless used topically  Use will cause blurred vision for 24 hours

51. ACTION OF ATROPINE ON SMOOTH MUSCLE

52. EFFECTS ON EXOCRINE GLANDS

53. STOPPING ATROPINE  Endpoints  Reduction in secretions (muscarinic effects)  Reduction in chest tightness (muscarinic effects)  Patient able to breathe comfortably on his/her own  Do not titrate to  Heart rate (variable; not an indicator of severity of exposure)  Miosis (may persist for up to 6 weeks despite atropine)  Twitching or fasciculations (nicotinic effects)

54. OXIMES  Effects at nicotinic sites  Increase skeletal muscle strength  No clinical effects at muscarinic sites

55. ACTION OF PRALIDOXIME CHLORIDE (2-PAM Cl)

56. OXIMES  Remove agent from enzyme, unless aging has occurred  Aging: agent-enzyme complex changes  Oximes cannot reactivate enzyme  Aging times: GD 2 min GB 3 to 4 hours Others longer

57. AGING OF THE NERVE AGENT- ACHE COMPLEX

58. OXIMES  Other countries have different ones  England: P2S  Some European countries: obidoxime  Israel: TMB4  Japan: 2-PAMI

59. 2-PAM Cl DOSE  NAAK (MARK I): contains 600 mg  One or three Combopens; repeat in one hour  IV: One gram slowly (20 to 30 min)  Repeat in one hour

60. SEIZURES  Without pyridostigmine  Not prolonged  Anticonvulsant seldom necessary  Prolonged after pyridostigmine  Possible brain damage from prolonged seizures  Anticonvulsant needed (diazepam)  Give diazepam to any severe casualty

61. RECOVERY  Severe casualty:  Without complications, conscious, breathing, in 2 to 3 hours

62. RETURN TO DUTY  Dose-dependent, need dependent  Could be hours with minor exposure, great need  Many days after severe exposure  Consider:  Vision  Minor, subtle mental effects

63. MARK I AUTO-INJECTOR

64. MILD VAPOR EXPOSURE  Miosis, rhinorrhea  Rx: Probably none unless rhinorrhea is severe  Atropine IM will not help miosis

65. MODERATE VAPOR EXPOSURE  Miosis, rhinorrhea, moderate or severe dyspnea  Walking and talking  Rx: 1 MARK I (if dyspnea is quite severe: 2 MARK Is)

66. SEVERE VAPOR EXPOSURE  Unconscious, or  Seizing or post-ictal, or  Clinical effects in two or more systems (airway, GI, muscular, CNS)

67. SEVERE VAPOR EXPOSURE  Rx: 3 MARK Is and diazepam ASAP  Ventilation  Rx even after cardiac arrest

68. MILD LIQUID EXPOSURE  Localized twitching, sweating  Rx: 1 MARK I (agent has been absorbed)

69. MODERATE SKIN EXPOSURE  GI effects: vomiting, diarrhea, cramps  Rx: 1 MARK I  Watch carefully for 18 hours

70. SEVERE SKIN EXPOSURE  Unconscious, or  Seizing or post-ictal, or  Clinical effects in two or more  Clinical effects in two or more systems (airway, GI, muscular, CNS)

71. SEVERE SKIN EXPOSURE  Rx: 3 MARK Is and diazepam  Ventilation  Rx after cardiac arrest

72. NERVE AGENTS: SUMMARY  Highly toxic, rapid acting  Convert acetylcholine into a poison; create cholinergic crisis  Treatable with specific therapy  Therapy must be timely (FAST!) and may be life-saving