2. Antidotes for cardiovascular drug poisoning New York University Department of Emergency Medicine/Medical Toxicology David H. Jang Assistant Professor Masters of Science Degree in Clinical Investigation (K30) Clinical and Translational Science Institute (CTSI) *Funded by the American Academy of Clinical Toxicology Junior Investigator Research Grant and also supported in part by grant 1UL1RR029893 from the National Center for Research Resources, National Institutes of Health.

3. Case 44 year-old man presents with a “overdose” after an argument with his mother Patient obtained these medications from his mother who he still lives with in her basement

4. Case Vitals on presentation: Blood pressure: 140/90 mmHG Heart rate: 90 BPM Respiratory rate: 12 Temperature: 98.6 Oxygen saturation: 100% RA

5. Case 6 hours later…

6. Case Repeat Vitals: Blood pressure: 85/40 mmHG Heart rate: 40 BPM Respiratory rate: 20 Temperature: 98.6 Oxygen saturation: 100% RA

7. Case Intubated Hemodynamic support On norepinephrine On dopamine On epinephrine Still hypotensive…

8. Options?

10. Antidotes for cardiovascular drug poisoning

11. Cardiovascular drug class Antihypertensives Imidazolines Beta-blockers Calcium channel blockers ACE-Is and ARBs Cardioactive steroids Digoxin Antidysrhythmics Flecainide

12. Cardiovascular drug class Antihypertensives Imidazolines Beta-blockers Calcium channel blockers ACE-Is and ARBs Cardioactive steroids Digoxin Antidysrhythmics Flecainide

13. Not all things are created equal…

14. Beta-blockers Non-selective Carvedilol B 1 -selective Atenolol Esmolol Intrinsic sympathomimetic Pindolol

15. Beta-blockers Potassium channel blockers Sotalol Membrane-stabilizing Propanolol

16. Calcium channel blockers Phenylalkylamine Verapamil Benzothiazepine Diltiazem Dihydropyridines Nifedipine Amlodipine Nicardipine

17. Epidemiology

21. Beta and calcium channel blocker poisoning Clinical Features Bradycardia Hypotension Management Isotonic fluids Glucagon Inotropes/Pressors High-insulin Lipid emulsion

22. Beta and calcium channel blocker poisoning Clinical Features Bradycardia Hypotension Management Isotonic fluids Glucagon Inotropes/Pressors High-insulin Lipid emulsion

23. Beta and calcium channel blocker poisoning Clinical Features Bradycardia Hypotension Management Isotonic fluids Glucagon Inotropes/Pressors High-insulin Lipid emulsion

24. High insulin-euglycemic therapy (HIE)

25. Historical use Glucose-insulin- potassium (GIK) Acute myocardial infarction Heart failure Myocardium

26. Background Hallmark of BB and CCB poisoning Bradycardia Vasodilation Decreased contractility

27. Background Altered myocardial physiology Hyperglycemia (pancreas/liver) Altered myocardial substrate use Inhibition of lactate oxidation

28. Mechanism of action Alters ions homeostasis (potassium/calcium/so dium) Metabolic support Increase lactate uptake Epi and glucagon promote FFA use (increase energy)

29. Experimental evidence

30. Groups 1. Control: (0/6) 2. Epi: (4/6)  (2/4) 3. HIE: (6/6)  (6/6) 4. Glucagon: (3/6)  (0/3)

31. Experimental evidence Groups 1. Control: (0/6) 2. Epi: (4/6)  (2/4) 3. HIE: (6/6)  (6/6) 4. Glucagon: (3/6)  (0/3)

32. Clinical experience

34. Adverse events Hypoglycemia Hypokalemia

35. Treatment guidelines

36. Intralipid

37. Background Triglycerides and phospholipids Primary triglycerides composed of linoleic, linolenic, and stearic acid pH 8, isotonic, various concentrations availiable (20% is primarily used)

38. Mechanism of action 1. Modulation of intracellular metabolism 2. Lipid sink 3. Activation of ion channels

39. Experimental evidence

41. Clinical experience

42. Adverse events

44. Treatment guidelines www.lipidrescue.org

45. Treatment guidelines

46. Summary Consider HIE early for suspected CCB poisoning Consider lipid emulsion when a patient is perimortem with suspected lipid-soluble medication

47. Methylene blue (MB)

48. Methylene blue Sentinel node detection Acquired methemoglobinemia Vasodilatory shock Anaphylaxis Sepsis

49. Nitric oxide synthase

50. Physiology of vascular tone

51. The evidence for MB

52. Mechanism of action

53. Vasodilatory shock from overdose?

54. Why calcium channel blockers?

56. Mechanism of action

57. So to test this…

58. Methods Design: Controlled, blinded animal design Subjects: Adult Sprague-Dawley rats (300-600 grams) Preparation (Instrumentation/sedation) Protocol: Phase 1: Dose-finding Phase 2: Methylene blue

59. Protocol summary and timeline Phase 1: Amlodipine dose determination 4 mg/kg: Incrementally increase dose 50% and decrease 50% (5 rats per group – 1, 2, 4, 6, 8 mg/kg) End-point: Decrease of mean arterial pressure to10% of baseline

60. Amlodipine dose

61. Protocol summary and timeline Group 1: Amlodipine  Normal saline (Control group) Group 2: Amlodipine  Methylene Blue (Treatment group)

62. Protocol summary and timeline BaselineAmlodipine MB (2 mg/kg) or saline 0 mins180 mins Phase 2: Methylene blue treatment 15 min5 min 3-hours or until death Group 1: Amlodipine  Normal saline (Control group) Group 2: Amlodipine  Methylene Blue (Treatment group)

63. Results Methylene blue-Pending Normal Saline-Pending

64. Questions?