Management of Cardiovascular Overdoses: Pharmacophysiology and Expert Solutions

1. INSTITUTE OF CRITICAL CARE MEDICINE ROYAL CARE SUPER SPECIALITY HOSPITAL

2. ACKNOWLEDGEMENT DR. RAM E RAJAGOPALAN DR.M.N. SIVAKUMAR INSTITUTE OF CRITICAL CARE MEDICINE, RCH, CBE

3. CALCIUM CHANNEL BLOCKERS & BETA BLOCKERS Dr. S.LAKSHMIKANTHCHARAN MD.,IDCCM.,EDIC Consultant Intensivist, RCH, Neelambur

4. OVERVIEW • Pharmacophysiology • Overdose • Clinical Manifestations • Management INSTITUTE OF CRITICAL CARE MEDICINE, RCH, CBE

5. PROBLEM STATEMENT • Poison-induced cardiogenic shock (PICS) is common • Overdoses of beta-blockers (BBs) and calcium channel blockers (CCBs) account for over 65% of deaths from all cardiovascular medications. • BB toxicity is the commonest cause of PICS in America • CCB overdose is less frequent, but is the cardiovascular agent with the highest mortality rate in America, responsible for 48% of all deaths from cardiovascular agents. 2012 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 30th Annual Report. Mowry JB, Spyker DA, Cantilena LR Jr, Bailey JE, Ford M Clin Toxicol (Phila). 2013 Dec; 51(10):949-1229 INSTITUTE OF CRITICAL CARE MEDICINE, RCH, CBE

6. PROBLEM STATEMENT • The most commonly prescribed anti hypertensive drugs especially in India • The ease of availability • Management of patients following overdose of these drugs can be difficult INSTITUTE OF CRITICAL CARE MEDICINE, RCH, CBE

7. PHARMACOPHYSIOLOGY INSTITUTE OF CRITICAL CARE MEDICINE, RCH, CBE

8. TOXICOKINETICS OF CCB The Calcium Channel • Different types – focus on L-type channel. • A voltage - gated channel found in cardiac myocytes, pacemaker cells, vascular smooth muscle, and on beta islet cells in the pancreas. • When the cell is depolarized, it allows for calcium influx and initiates different intracellular pathways. • Smooth muscle - calcium binds directly to calmodulin contraction. • Pancreas - the calcium allows for exocytosis of insulin. INSTITUTE OF CRITICAL CARE MEDICINE, RCH, CBE

9. IN PACEMAKER CELLS IN CARDIAC MYOCYES INSTITUTE OF CRITICAL CARE MEDICINE, RCH, CBE

10. In myocytes, When the cell is depolarized  the L-type calcium channel opens calcium moves into the cytoplasm  Calcium then binds the ryanodine receptor on the sarcoplasmic reticulum  triggering a large calcium efflux from the SR into the cell  Calcium bind troponin leads to contraction of the actin and myosin filiments INSTITUTE OF CRITICAL CARE MEDICINE, RCH, CBE

11. BLOCKAGE OF L-TYPE CHANNELS IN…… INSTITUTE OF CRITICAL CARE MEDICINE, RCH, CBE

12. SELECTED CHARACTERISTICS OF SOME CA+ CHANNEL BLOCKERS INSTITUTE OF CRITICAL CARE MEDICINE, RCH, CBE

13. MECHANISM OF CARDIOTOXICITY IN CCB OVERDOSE During stress cardiac myocytes switch from fatty acids to glucose for energy production  At high doses - decreased insulin  decreases cardiac carbohydrate metabolism  lack of fuel for aerobic energy production shift back to fatty acid oxidation within the cells which might not be adequate  Impaired energy production  negative inotropy and chronotropy  profound shock and metabolic acidosis INSTITUTE OF CRITICAL CARE MEDICINE, RCH, CBE

14. TOXICOKINETICS OF BB The Beta-Receptor • an adrenergic receptor • the beta-1 receptor – In heart  Coupled to a stimulatory G protein  Activates adenylate cyclase  ATP to cAMP  Stimulates protein kinase A  Phosphorylate or activate, the L-type calcium channel PKA also phosphorylates phospholamban  Increased intracellular calcium  Increased inotropy and chronotropy. INSTITUTE OF CRITICAL CARE MEDICINE, RCH, CBE

15. The beta-2 receptor : on vascular smooth muscle - vasodilation. In skeletal muscle - glycogenolysis and potassium uptake In liver - glycogenolysis and gluconeogenesis In lungs - bronchodilation. • The beta-3 receptor is involved in lipolysis, and is not significant INSTITUTE OF CRITICAL CARE MEDICINE, RCH, CBE

16. Greene Shepherd, Treatment of poisoning caused by β-adrenergic and calcium-channel blockers, American Journal of Health-System Pharmacy, Volume 63, Issue 19, 1 October 2006, Pages 1828–1835, INSTITUTE OF CRITICAL CARE MEDICINE, RCH, CBE

17. INSTITUTE OF CRITICAL CARE MEDICINE, RCH, CBE

18. OVERDOSE • Receptor selectivity is lost • Effects not normally seen at therapeutic doses can occur. • In overdose, β-blockers and CCBs often have similar presentation and there is much overlap in treatment. • Cardiac toxicity: • Negative inotropy - myocardial depression • Negative chronotropy - sinus bradycardia • Negative dromotropy - atrioventricular node blockade • Effects on vascular sm ms tone: • Decreased afterload • Systemic hypotension • Coronary vasodilation INSTITUTE OF CRITICAL CARE MEDICINE, RCH, CBE

19. Greene Shepherd, Treatment of poisoning caused by β-adrenergic and calcium-channel blockers, American Journal of Health-System Pharmacy, Volume 63, Issue 19, 1 October 2006, Pages 1828–1835, INSTITUTE OF CRITICAL CARE MEDICINE, RCH, CBE

20. Olson KR, Erdman AR, Woolf AD et al. Calcium channel blocker ingestion: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol . 2005; 43:797–822. INSTITUTE OF CRITICAL CARE MEDICINE, RCH, CBE

21. CLINICAL PRESENTATION INSTITUTE OF CRITICAL CARE MEDICINE, RCH, CBE

22. CLINICAL PRESENTATION • Time since ingestion and the severity of the overdose • Asymptomatic decompensate rapidly. • Obtunded or in cardiac arrest. • Cardiovascular signs  Hypotension and bradycardia cardiogenic shock. • Conduction disturbances  mild interval prolongation/ CHB • Arrhythmias, QT prolongation and torsades de pointes may be encountered • CNS decreased or altered mental status, obtundation,coma and seizures. • Metabolic findings - BB hypoglycemia CCB hyperglycemia. INSTITUTE OF CRITICAL CARE MEDICINE, RCH, CBE

23. MANIFESTATIONS AND COMPLICATIONS OF BETA-BLOCKER OVERDOSE IN ORDER OF DECREASING FREQUENCY INSTITUTE OF CRITICAL CARE MEDICINE, RCH, CBE

24. DIFFERENTIAL DIAGNOSIS The differential includes toxicity from these agents: • Digoxin • Imidazoline (e.g., clonidine) • Opiate • Sedative hypnotic • Cholinergic toxicity. INSTITUTE OF CRITICAL CARE MEDICINE, RCH, CBE

25. INSTITUTE OF CRITICAL CARE MEDICINE, RCH, CBE

26. HISTORY • The time of ingestion • The specific name of the medication • Co - ingestants • The number of pills ingested • The exact amount of drug in each tablet • The formulation (i.e., immediate release vs. sustained release) • Alcohol, or illicit drugs • Patients who are on other cardioactive medication INSTITUTE OF CRITICAL CARE MEDICINE, RCH, CBE

27. INITIAL CARE & GASTRIC DECONTAMINATION ABC • Gastric lavage – Consider time since ingestion – Benefit outweigh risk? • Activated charcoal (1 gm/kg) if appropriate –within 60 minutes of ingestion( 2 hrs - SR preparations) – Patient is cooperative with intact airway – No good evidence for repeat doses • Whole-bowel irrigation – Evidence for improved outcome is lacking – Has been advocated for sustained-release preparations – Polyethylene glycol solution, orally/ NG at 1 to 2 L/hour INSTITUTE OF CRITICAL CARE MEDICINE, RCH, CBE

28. INVESTIGATIONS • 12 lead ECG • Electrolytes • BUN / Cr • Digoxin level if concomitant toxicity suspected • ABG • Lactic acid • Echocardiogram • CXR INSTITUTE OF CRITICAL CARE MEDICINE, RCH, CBE

29. TREATMENT OF BETA BLOCKER POISONING • PHASE 1 – RESUSCITATION PHASE • Boluses of atropine • Glucagon • Fluids • PHASE 2 – STABILISATION PHASE • Glucagon infusion • High dose insulin – euglycemia • Catecholamines • Phosphodiesterase inhibitors • Intravenous pacing • PHASE 3 – SALVAGE THERAPY • Hemodialysis • Intralipid • IABP • ECMO INSTITUTE OF CRITICAL CARE MEDICINE, RCH, CBE

30. TREATMENT OF CCB POISONING • PHASE 1 – RESUSCITATION PHASE • Isotonic iv fluids • calcium (1D) • PHASE 2 – STABILISATION PHASE • Catecholamine infusion, invasive monitoring (1D) • Intravenous calcium (1D) • High dose insulin glucose infusion (1D) • intravenous pacing (2D) • PHASE 3 – SALVAGE THERAPY • Lipid emulsion (2D) • Cardiac supports- aortic balloon, ECMO (2D) CRITICAL CARE MEDICINE: MARCH 2017 - VOLUME 45 INSTITUTE OF CRITICAL CARE MEDICINE, RCH, CBE

31. IV FLUIDS MOA Expands intravascular volume and counteracts vasodilation to a certain extent EVIDENCES Standard practice. In mild cases, this may be all that is needed to reverse toxicity DOSE Around 20 ml/kg crystalloids ADR Pulmonary edema INSTITUTE OF CRITICAL CARE MEDICINE, RCH, CBE

32. CRYSTALLOIDS INSTITUTE OF CRITICAL CARE MEDICINE, RCH, CBE

33. ATROPINE ACLS MOA By antagonism of muscarinic receptors, there may be less inhibition of adenylatecyclase in the heart causing more cAMP. EVIDENCES For symptomatic bradycardia as per ACLS.Itsefficacy is minimal, and it is unlikely to improve hemodynamics. DOSE Adult dose is 0.5-1 mg IV repeated to maximum of 3 mg ADR Not much INSTITUTE OF CRITICAL CARE MEDICINE, RCH, CBE

34. VASOPRESSORS Activates alpha and beta receptors competes with beta-blockers In CCB pts, beta activation can provide some activation of the L-type channels, peripheral alpha-1-receptor activation causes vasoconstriction MOA EVIDENCES Standard practice for any hypotension not responding to fluids DOSE As patients are resistant to these drugs, the initial dose should be high and the infusion rates should be rapidly titrated to effect. ADR Arrythmias, hyperlactatemia, limb ischemia, bowel ischemia INSTITUTE OF CRITICAL CARE MEDICINE, RCH, CBE

35. VASOPRESSORS INSTITUTE OF CRITICAL CARE MEDICINE, RCH, CBE

36. IN A NUTSHELL INSTITUTE OF CRITICAL CARE MEDICINE, RCH, CBE

37. CALCIUM MOA An attempt to raise serum calcium levels  it overcomes the blockade of the L-type channel by calcium channel blockers and the downstream effects of beta-blockade increases inotropy and stroke volume. EVIDENCES Success of this therapy is inconsistent. Multiple case reports and animal studies show that calcium chloride infusion improves inotropy, hemodynamics but heart rate is unaffected. DOSE Bolus of calcium gluconate 10% 3 g (30 mL) or calcium chloride 10% 1 g (10 mL), repeated as needed. Maintain with infusion of 0.2-0.5 mL/kg/hr 10% CaCl or 0.6-1.5 mL/kg/hr calcium gluconate ADR Do not exceed Ca++ level of 14 mg/dL or twice normal levels of ionized Ca Use central line for CaCl infusion to avoid tissue necrosis. Watch for arrhythmias with rapid infusion Howarth DM, Dawson AH, Smith AJ, et al. Calcium channel blocking drug overdose: An Australian series. Hum Exp Toxicol. 1994;13:161–166 Henry M, Kay MM, Viccellio P. Cardiogenic shock associated with calcium-channel and beta blockers: Reversal with intravenous calcium chloride. Am J Emerg Med. 1985;3:. INSTITUTE OF CRITICAL CARE MEDICINE, RCH, CBE

38. IN A NUTSHELL INSTITUTE OF CRITICAL CARE MEDICINE, RCH, CBE

39. GLUCAGON MOA Activates adenylate cyclase, increasing cyclic AMP independently of the beta-adrenergic receptor. It increases inotropy and chronotropy in animal models. EVIDENCES In animal models of CCB and BB poisoning, glucagon exerts its effect primarily as a positive chronotrope, with little or no effect on BP . A number of positive case reports have been reported in BB and CCB poisoning, but not as a sole agent. IV bolus of 50 mcg/kg (max 10 mg) over 1-2 minutes short (20-minute) half-life, infusion of 2 to 5 mg/hrstarted immediately diuted in 5% dextrose DOSE ADR gastrointestinal (e.g. Nausea, Vomiting), mild hyperglycemia, hypokalemia, and allergic reactions. Bailey B. Glucagon in beta‐blocker and calcium channel blocker overdoses: a systematic review. J Toxicol Clin Toxicol 2003; 41: 595–602. Kosinski EJ, Stein N, Malindzak GS, Boone E. Glucagon and propranolol (Inderal) toxicity. N Engl J Med 1971; 285: 1325–5. INSTITUTE OF CRITICAL CARE MEDICINE, RCH, CBE

40. IN A NUTSHELL INSTITUTE OF CRITICAL CARE MEDICINE, RCH, CBE

41. HIGH DOSE INSULIN EUGLYCEMIA (HDIE) THERAPY MOA Normally cardiac cells acquire energy via fatty acid oxidation, but need glucose in times of stress, such as toxin-induced cardiogenic shock. Insulin improves glucose utilization in the heart. EVIDENCES Most effective treatment on literature There are no randomized controlled human trials. Human case reports with CCB shows improved survival, although in severe cases, other treatments should be used in conjunction. DOSE 1 u/kg bolus with a dextrose bolus of 0.5 g/kg  Infusion of 0.5 unit/kg/hrwith a dextrose infusion of 0.5 g/kg/hr, which is titrated to effect. ADR Hypoglycemia Hypokalemia Mild vasodilation No effect on heart rate Espinoza TR, Bryant SM, Aks SE. Hyperinsulin therapy for calcium channel antagonist poisoning: a seven‐year retrospective study. Am J Ther 2013; 20: 29–31. INSTITUTE OF CRITICAL CARE MEDICINE, RCH, CBE

42. IN A NUTSHELL INSTITUTE OF CRITICAL CARE MEDICINE, RCH, CBE

43. RESCUE THERAPIES • Transcutaneous or transvenous pacing (If HR < 40). Electrical capture is not always successful & if capture does occur BP is not always restored. • Intralipid • Phosphodiesterase inhibitors • IABP • Cardiopulmonary bypass • ECMO • Hemodialysis INSTITUTE OF CRITICAL CARE MEDICINE, RCH, CBE

44. INTRALIPID MOA Forms a “lipid sink” around lipophilic drug molecules making them ineffective Fatty acids from the emulsion provide the myocardium with an energy source EVIDENCES No human RCTs, few animal studies and multiple human case reports - appears to have contributed to recovery from cardiogenic shock or arrest. American College of Toxicologist usage suggestion DOSE 20 % Intralipid emulsion 1.5 ml/kg initial bolus ( rpt q3-5min in cardiac arrest) 0.25 ml/kg/min for 30 – 60 min Max – 8 mg/kg ADR Anaphylactoid reaction Fat overload syndrome ( coagulopathy, jaundice and lipid accumulation in liver) Intravenous lipid emulsion in the management of amlodipine overdose.MeaneyCJ, Sareh H, Hayes BD, GonzalesJP HospPharm. 2013 Nov; 48(10):848-54. INSTITUTE OF CRITICAL CARE MEDICINE, RCH, CBE

45. IN A NUTSHELL INSTITUTE OF CRITICAL CARE MEDICINE, RCH, CBE

46. PHOSPHODIESTERASE INHIBITORS MOA Phosphodiesterase (PDE) inhibition leads to increased cAMP without activation of the beta-receptor. EVIDENCES Animal studies show PDE inh improve inotropy with little effect on heart rate. When all other therapies are failing, a trial may be considered. DOSE Milrinone 50-mcg/kg IV bolus, then 0.25-1 mcg/kg/min infusion. Amrinone 75-mcg/kg IV bolus, then 2- 20 mcg/kg/min infusion. ADR Also have a vasodilating effect, and this may counteract their inotropic effects on blood pressure Kollef MH. Labetalol overdose successfully treated with amrinone and alpha‐adrenergic receptor agonists. Chest 1994; 105: 626–7. INSTITUTE OF CRITICAL CARE MEDICINE, RCH, CBE

47. IN A NUTSHELL INSTITUTE OF CRITICAL CARE MEDICINE, RCH, CBE

48. EXTRACORPOREAL TREATMENT • Invasive Procedures. • Given the reversible nature of many poisonings, ECMO can allow time for drug redistribution and/or metabolism to a point where cardiac function in an otherwise healthy heart is restored. • When other treatments fail, even when the patient is in cardiac arrest, there are case reports of using an IABP/ ECMO with success. • If the patient is symptomatic following overdose, consult cardiology early, so that if the patient continues to deteriorate, these invasive procedures can be performed • ECMO are not very effective in cases of refractory vasodilatory shock where cardiac output is already increased Baud FJ, Megarbane B, Deye N, Leprince P. Clinical review: aggressive management and extracorporeal support for drug‐induced cardiotoxicity. Crit Care 2007; 11: 207. Megarbane B, Deye N, Baud FJ. Extracorporeal Life‐Support for Acute Drug‐induced Cardiac Toxicity. In: Year Book of Intensive Care and Emergency Medicine, 1st edn. Berlin, Heidelberg: Springer, 2008; 179–89 INSTITUTE OF CRITICAL CARE MEDICINE, RCH, CBE

49. HAEMODIALYSIS • Hemodialysis - useful in low lipid soluble & low protein binding beta blockers. • Atenolol is < 5% protein bound so dialyzable along with nadolol, sotalol & acebutalol. • Consider hemodialysis only when glucagon & other pharmacotherapy fails. • CCB are highly protein bound so hemodialysis not useful. INSTITUTE OF CRITICAL CARE MEDICINE, RCH, CBE

50. CONSENSUS RECOMMENDATIONS CRITICAL CARE MEDICINE: MARCH 2017 - VOLUME 45 INSTITUTE OF CRITICAL CARE MEDICINE, RCH, CBE