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Slide 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. Slide 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 Slide 4 Case Vitals on presentation: Blood pressure: 140/90 mmHG Heart rate: 90 BPM Respiratory rate: 12 Temperature: 98.6 Oxygen saturation: 100% RA Slide 5 Case 6 hours later Slide 6 Case Repeat Vitals: Blood pressure: 85/40 mmHG Heart rate: 40 BPM Respiratory rate: 20 Temperature: 98.6 Oxygen saturation: 100% RA Slide 7 Case Intubated Hemodynamic support On norepinephrine On dopamine On epinephrine Still hypotensive Slide 8 Options? Slide 9 Slide 10 Antidotes for cardiovascular drug poisoning Slide 11 Cardiovascular drug class Antihypertensives Imidazolines Beta-blockers Calcium channel blockers ACE-Is and ARBs Cardioactive steroids Digoxin Antidysrhythmics Flecainide Slide 12 Cardiovascular drug class Antihypertensives Imidazolines Beta-blockers Calcium channel blockers ACE-Is and ARBs Cardioactive steroids Digoxin Antidysrhythmics Flecainide Slide 13 Not all things are created equal Slide 14 Beta-blockers Non-selective Carvedilol B 1 -selective Atenolol Esmolol Intrinsic sympathomimetic Pindolol Slide 15 Beta-blockers Potassium channel blockers Sotalol Membrane-stabilizing Propanolol Slide 16 Calcium channel blockers Phenylalkylamine Verapamil Benzothiazepine Diltiazem Dihydropyridines Nifedipine Amlodipine Nicardipine Slide 17 Epidemiology Slide 18 Slide 19 Slide 20 Slide 21 Beta and calcium channel blocker poisoning Clinical Features Bradycardia Hypotension Management Isotonic fluids Glucagon Inotropes/Pressors High-insulin Lipid emulsion Slide 22 Beta and calcium channel blocker poisoning Clinical Features Bradycardia Hypotension Management Isotonic fluids Glucagon Inotropes/Pressors High-insulin Lipid emulsion Slide 23 Beta and calcium channel blocker poisoning Clinical Features Bradycardia Hypotension Management Isotonic fluids Glucagon Inotropes/Pressors High-insulin Lipid emulsion Slide 24 High insulin-euglycemic therapy (HIE) Slide 25 Historical use Glucose-insulin- potassium (GIK) Acute myocardial infarction Heart failure Myocardium Slide 26 Background Hallmark of BB and CCB poisoning Bradycardia Vasodilation Decreased contractility Slide 27 Background Altered myocardial physiology Hyperglycemia (pancreas/liver) Altered myocardial substrate use Inhibition of lactate oxidation Slide 28 Mechanism of action Alters ions homeostasis (potassium/calcium/so dium) Metabolic support Increase lactate uptake Epi and glucagon promote FFA use (increase energy) Slide 29 Experimental evidence Slide 30 Groups 1. Control: (0/6) 2. Epi: (4/6) (2/4) 3. HIE: (6/6) (6/6) 4. Glucagon: (3/6) (0/3) Slide 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) Slide 32 Clinical experience Slide 33 Slide 34 Adverse events Hypoglycemia Hypokalemia Slide 35 Treatment guidelines Slide 36 Intralipid Slide 37 Background Triglycerides and phospholipids Primary triglycerides composed of linoleic, linolenic, and stearic acid pH 8, isotonic, various concentrations availiable (20% is primarily used) Slide 38 Mechanism of action 1. Modulation of intracellular metabolism 2. Lipid sink 3. Activation of ion channels Slide 39 Experimental evidence Slide 40 Slide 41 Clinical experience Slide 42 Adverse events Slide 43 Slide 44 Treatment guidelines www.lipidrescue.org Slide 45 Treatment guidelines Slide 46 Summary Consider HIE early for suspected CCB poisoning Consider lipid emulsion when a patient is perimortem with suspected lipid-soluble medication Slide 47 Methylene blue (MB) Slide 48 Methylene blue Sentinel node detection Acquired methemoglobinemia Vasodilatory shock Anaphylaxis Sepsis Slide 49 Nitric oxide synthase Slide 50 Physiology of vascular tone Slide 51 The evidence for MB Slide 52 Mechanism of action Slide 53 Vasodilatory shock from overdose? Slide 54 Why calcium channel blockers? Slide 55 Slide 56 Mechanism of action Slide 57 So to test this Slide 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 Slide 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 Slide 60 Amlodipine dose Slide 61 Protocol summary and timeline Group 1: Amlodipine Normal saline (Control group) Group 2: Amlodipine Methylene Blue (Treatment group) Slide 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) Slide 63 Results Methylene blue-Pending Normal Saline-Pending Slide 64 Questions?