1. Toxicity mediated by interference with membrane pumps - underlying mechanisms of cardiac glycoside toxicity Michael Eddleston Scottish Poisons Information Bureau Royal Infirmary of Edinburgh, UK

3. Cardiac glycoside poisoning Epidemiology of cardiac glycoside poisoning Standard treatment = pharmacokinetics Mechanisms of toxicity Possibilities for treatment that result from this knowledge Future research??

5. Cardiac glycoside medication poisoning Deaths uncommon in industrialised countries Schaper et al Eur J Intern Med 2006;17:474. GIZ-Nord Poison Center consulted in 168,000 cases. 142 deaths (0.08% of cases) None due to cardiac glycosides AAPCC data from USA 2005 Clin Tox 2006;44:803. 61 poison centres consulted in 2,424,180 cases 1261 deaths (0.05% of cases) 20 (1.6%) primarily due to cardiac glycosides (10 due to therapeutic error, 3 ADR, only 3 intentional)

9. Self-poisoning in north central Sri Lanka Prospective cohort of acutely poisoned patients started in March 2002 in 2 district hospitals. Now contains over 13,000 patients. Up to mid-2005: 8383 cases 98% due to self-harm Pesticides:3848 (45.9% of total) Oleander seeds:2423 (28.9% of total) Other common poisons: medicines & hydrocarbons All treated using a standard protocol

10. Case fatality for different classes of poison

11. Case series of oleander poisoning Jaffna, Sri Lanka, 1980 - 170 patients over 3 years, with 7 deaths (CFR 4.1%). Bankura, W Bengal, 1985 – 300 patients over 5 years, with 14 deaths (CFR 4.7%). Anuradhapura, Sri Lanka, 1995 – 79 patients over 4 months, with 6 deaths (CFR 7.6%) North Central Province, Sri Lanka 2005 – 2423 patients over 3 years, with 109 deaths (CFR 4.5%)

12. Symptoms of substantial oleander poisoning (n=66) Cardiac dysrhythmias100% Nausea100% Vomiting100% Weakness88% Fatigue86% Diarrhoea80% Dizziness67% Abdominal Pain59% Visual Symptoms36% Headache34% Sweating20% Confusion19% Fever and/or Chills5% Anxiety3% Abnormal Dreams3%

13. Standard treatment Only two interventions have been carefully studied Anti-digoxin/digitoxin Fab Activated charcoal Both these treatments work by affecting the pharmacokinetics of the cardiac glycoside, by: ospeeding elimination and/or oreducing absorption

14. Standard treatment Only two interventions have been carefully studied Anti-digoxin/digitoxin Fab Activated charcoal Both these treatments work by affecting the pharmacokinetics of the cardiac glycoside, by: ospeeding elimination and/or oreducing absorption

15. The introduction of Fab fragments for digoxin poisoning first reported in humans in April 1976 reversal of advanced digoxin intoxication with Fab fragments of digoxin-specific ovine antibodies Ingested dose = 22.5 mg of digoxin serum potassium initially 8.7 mmol/l

16. Time course of : total serum digoxin ( ) Free serum digoxin ( ) Fab fragments ( ) serum potassium ( ) after iv administration of DA in a 39-year-old man with severe digoxin poisoning. Smith TW et al. Reversal of advanced digoxin intoxication with Fab fragments of digoxin- specific antibodies. N Engl J Med 1976;294:797-800.

17. Effect of Fab in oleander poisoning

19. Effect of anti-digoxin Fab on dysrhythmias

20. Effect of Fab on serum potassium

21. Standard treatment Only two interventions have been carefully studied Anti-digoxin/digitoxin Fab Activated charcoal Both these treatments work by affecting the pharmacokinetics of the cardiac glycoside, by: ospeeding elimination and/or oreducing absorption

22. Treated with Activated Charcoal vs Not Treated with Activated Charcoal

23. Comparison of two published RCTs de Silva MDAC 5/201 [2·5%] vs SDAC 16/200 [8%] RR 0.31 (95% CI 0.12 to 0.83) SACTRC MDAC 22/505 [4·4%] vs SDAC 24/505 [4.8%] RR 0.92 (95% CI 0.52 to 1.60) Fixed effects model, test of heterogeneity P=0.06 Why? Different regimen? Poor compliance?

24. Time from hospital admission to death in RCT

25. Standard treatment Only two interventions have been carefully studied Anti-digoxin/digitoxin Fab Activated charcoal Current situation: Anti-digoxin Fab are too expensive for widespread use The evidence for activated charcoal is ? negative Are there other options? Here we need to understand the mechanism of toxicity

26. Ion channels of cardiac muscle

27. Function of Na+/K+ ATPase

28. Effect of cardiac glycosides

29. Consequences of cardiac glycoside binding 1 Rises in intracellular Ca 2+ and Na + concentrations Partial membrane depolarisation and increased automaticity (QTc interval shortening) Generation of early after-depolarisations (u waves) that may trigger dysrhythmias Variable Na + channel block, altered sympathetic activity, & increased vascular tone.

30. Consequences of cardiac glycoside binding 2 Decrease in conduction through the SA and AV nodes Due to increase in vagal parasympathetic tone and by direct depression of this tissue Seen as decrease in ventricular response to SV rhythms and PR interval prolongation In very high dose poisoning, Ca 2+ load may overwhelm the sarcoplasmic reticulum’s capacity to sequester it, resulting in systolic arrest – ‘stone heart’

31. Yellow oleander cardiotoxicity

32. Potassium effects 1 Hyperkalaemia is a feature of poisoning, due to inhibition of the Na + /K + ATPase. Causes hyperpolarisation of cardiac tissue, enhancing AV block. Study of 91 acutely digitoxin poisoned patients before use of anti-digoxin Fab (Bismuth, Paris): All with [K + ] >5.5 mmol/L died 50% of those with [K + ] 5.0-5.5 mmol/L died None of those with [K + ] <5.0 mmol/L died However, Rx of hyperkalaemia ‘does not improve outcome’

33. Potassium effects 2 Pre-existing hypokalaemia also inhibits the ATPase & enhances myocardial automaticity, increasing the risk of glycoside induced dysrhythmias Effect of hypokalaemia may be in part due to reduced competition at the ATPase binding site Hypokalaemia <2.5 mmol/L slows the Na pump, exacerbating glycoside induced pump inhibition.

34. What other treatment options are available? Anti-arrhythmics – lidocaine & phenytoin Atropine & pacemakers Correction of electrolyte abnormalities Correction of hyperkalaemia Fructose 1,6 diphosphate Unfortunately, as yet, no RCTs to guide treatment

35. Classic treatments Phenytoin/lidocaine – depress automaticity, while not depressing AV node conduction. Phenytoin reported to terminate digoxin-induced SVTs. Atropine – given for bradycardias. Temporary pacemaker – to increase heart rate, but cannot prevent ‘stone heart’. Also insertion of pacemaker may trigger VF in sensitive heart. Now not recommended where Fab is available.

36. Response of atropine-naïve oleander poisoned patients to 0.6mg of atropine

37. Response of atropine-naïve oleander poisoned patients to 0.6mg of atropine

38. Importance of the nervous system In animals, spinal cord transection reduces the toxicity of cardiac glycosides Administration of the  2-adrenoceptor agonist clonidine increases the dose of cardiac glycoside required to induce dysrhythmias and death. Inhibited by administration of yohimbine. Can this information be confirmed in humans? Is this partly how atropine is working?

39. Classic treatments Phenytoin/lidocaine – depress automaticity, while not depressing AV node conduction. Phenytoin reported to terminate digoxin-induced SVTs. Atropine – given for bradycardias. Temporary pacemaker – to increase heart rate, but cannot prevent ‘stone heart’. Also insertion of pacemaker may trigger VF in sensitive heart. Now not recommended where Fab is available.

40. Correction of electrolyte disturbances Hypokalaemia exacerbates cardiac glycoside toxicity therefore ? reasonable to replace K +. However, in acute self-poisoning (not acute on chronic), hypokalaemia is uncommon. Hypomagnesaemia. Serum [Mg 2+ ] is not related to severity in oleander poisoning. However, low [Mg 2+ ] will make replacing K + difficult. Theoretically, giving Mg 2+ will be beneficial but this was tried in Sri Lanka without clear benefit (but not RCT).

41. Serum potassium on admission

42. Correction of electrolyte disturbances Hypokalaemia exacerbates cardiac glycoside toxicity therefore ? reasonable to replace K +. However, in acute self-poisoning (not acute on chronic), hypokalaemia is uncommon. Hypomagnesaemia. Serum [Mg 2+ ] is not related to severity in oleander poisoning. However, low [Mg 2+ ] will make replacing K + difficult. Theoretically, giving Mg 2+ will be beneficial but this was tried in Sri Lanka without clear benefit (but not RCT).

43. Serum magnesium on admission

44. Correction of electrolyte disturbances Hypokalaemia exacerbates cardiac glycoside toxicity therefore ? reasonable to replace K +. However, in acute self-poisoning (not acute on chronic), hypokalaemia is uncommon. Hypomagnesaemia. Serum [Mg 2+ ] is not related to severity in oleander poisoning. However, low [Mg 2+ ] will make replacing K + difficult. Theoretically, giving Mg 2+ will be beneficial but this was tried in Sri Lanka without clear benefit (but not RCT).

45. Correction of hyperkalaemia - dangerous or beneficial?

48. Cerbera manghas poisoning (pink-eyed cerbera, odallam, kaduru, or sea mango)

49. Use of insulin/dextrose for hyperkalemia Van Deusen 2003 – single case. No effect – neither dangerous nor beneficial. Reports from India of ‘successfully’ treating yellow oleander poisoning with insulin dextrose when no other therapies were available. Oubaassine and colleagues 2006 – reported case of combined digoxin (17.5 mg) & insulin (50 iu) poisoning with no substantial cardiac effects and no hyperkalaemia. Might lowering [K+] > 5.5 mmol/L be beneficial???

50. Oubaassine 2006 – rat work Rats were infused with 0.625 mg/hr digoxin. After 20 mins, half received high dose glucose and insulin to keep glucose between 5.5 to 6.6 mmol/L. Time to death recorded Thirty minutes after digoxin infusion, plasma [K + ] had risen in control group compared to insulin glucose group: 6.9 ± 0.5 mmol/L vs 4.9 ± 0.3 mmol/L. Effect on clinically important outcomes?

51. Effect of insulin dextrose on survival

52. Fructose 1,6 diphosphate (FDP) 1 Intermediate of muscle metabolism – mechanism?? Markov 1999, Vet Hum Toxicol. Effect of FDP in dog Nerium oleander poisoning. 12 dogs infused with 40mg/kg oleander extract over 5min Then half the dogs were infused with 50mg/kg FDP by slow IV bolus, followed by constant infusions.

54. Fructose 1,6 diphosphate (FDP) 1 Intermediate of muscle metabolism – mechanism?? Markov 1999, Vet Hum Toxicol. Effect of FDP in dog Nerium oleander poisoning. 12 dogs infused with 40mg/kg oleander extract over 5min Then half the dogs were infused with 50mg/kg FDP by slow IV bolus, followed by constant infusions.

55. Response of dysrhythmias to FDP

56. Response of blood pressure to FDP

57. Response of plasma [K + ] to FDP

58. Conclusions Cardiac glycoside toxicity is a common global problem Anti-digoxin Fab are an effective PK Rx but expensive Treatments based on a mechanistic understanding may also be effective but none have been trialed, perhaps due to the effectiveness of Fab FDP – if found to be effective, its safety and price make it a very attractive future therapy. Unfortunately, we do not yet know how FDP works!