New Antidotes in Clinical Toxicology

1. New Antidotes in Clinical Toxicology William Darko, B.Pharm(Hons), Pharm.D. Director, Post Graduate Year – 1 Pharmacy Residency Program Clinical Pharmacist, Cardiovascular/Critical Care Services Associate Professor of Pharmacy Practice Assistant Professor of Medicine, Section of Clinical Pharmacology University Hospital, SUNY Upstate Medical University Syracuse, New York

2. Objectives • List the indication(s) for each antidote • Explain the clinical pharmacology of each antidote • Demonstrate understanding of clinical evidence supporting the choice of each antidote • Identify the side effects and monitoring parameters associated with each antidote • Understand the process of compounding or preparing each antidote for administration • Apply acquired knowledge to sampled questions

3. Background • 2007: 25th annual report of the AAPCC • Information reported by 61 centers • Reported 4,224,157 total cases • 2,482,041 human exposure cases • NYS updated list of antidotes – June 2009 • About 42 antidotes listed

5. Road Map

7. A 22 year old male was admitted to our institution after intentional overdose of an unknown quantity of acetaminophen tablets. He then called EMS and states that “I overdosed because I wanted attention from my girlfriend who is seeing another guy, please save me. I don’t want to die”. He was conscious on arrival to our emergency department but did complain of abdominal pain and nausea. A stat APAP level, BMP, and liver panel 6.5 hours post ingestion was reported as; APAP160 mcg/mL, AST 1554 U/L, Scr 0.9 mg/dL, BUN 15.9 mg/dL INR 1.20, PT 59 sec. The PCC was consulted and the recommendation was to start N – acetyl cysteine 1.What is the dose of NAC required for this patient? IV or oral? duration?? 2. What is the evidence for each route in this patient? 3.How should NAC be prepared for administration? 4.What adverse drug effects should you monitor?

9. Fatalities from APAP overdose are common but preventable by timely administration of NAC Rumack – Matthew Nomogram

11. Mechanism of Action of NAC

12. Each of these preventive mechanisms must be in place early. None is of benefit after NAPQI has initiated cell injury. There is an 8 hours window of opportunity

19. Intravenous Vs Oral NAC • The choice of oral vs IV NAC is complex • Each has advantages and disadvantages • IV and oral NAC are equally efficacious in treating APAP toxicity • Except established liver failure and pregnancy • Efficacy of oral NAC and IV NAC protocols are equivalent when started within 8 hours post ingestion • Decision on route should be based on ADE, safety, and ease of use but NOT efficacy

20. Conclusion • NAC is indicated for the treatment of APAP toxicity • IV NAC = oral NAC in efficacy • Best results when NAC is initiated within 8 hours post APAP ingestion • Preparation and delivery should be timely • Anaphylactoid reactions are rare with oral but occur with IV NAC

21. Intravenous Fat Emulsion (IFE) • Traditionally, IFE is used to provide nutrition in the form of free fatty acids to patients requiring Total Perenteral Infusion (TPN) • IFE is currently used in the treatment of toxicity due to local anesthetics and other lipid – soluble drugs • This therapy is currently investigational and not FDA approved in the United States

22. A 25 year old female with history of drug overdose, was admitted after ingesting an unknown quantity of her fathers amlodipine and acetaminophen tablets. At the time of presentation by the EMS her blood pressure was 80/49 mmHg, HR was 90 bpm. She was receiving normal saline at 150 mL/hour after a bolus of 1000 mL. She was lethargic at presentation with cold extremities. Norepinephrine infusion was started. Her laboratory values were as follows: • Scr 2.7 mg/dL, BUN 37 mg/dL, APAP level <10 mcg/mL, HCO3 17 mmol/L. LFT’s wnl. • PCC was consulted. 20% Fat emulsion was recommended. • What is the dose of IFE • How do you prepare a 20% IFE for the treatment of drug toxicity • What is the duration of therapy? • What side effects should you monitor? • Where is the evidence?

23. The Association of Anesthetics of Great Britain and Ireland. Guidelines for the management of Serves Local Anesthetic Toxicity. http://www.aagbi.org/publications/guidelines/docs/latoxicity07.pdf. Downloaded on June 27th 2009

24. The Association of Anesthetics of Great Britain and Ireland. Guidelines for the management of Severe Local Anesthetic Toxicity. http://www.aagbi.org/publications/guidelines/docs/latoxicity07.pdf. Downloaded on July 27th 2009

25. The Association of Anesthetics of Great Britain and Ireland. Guidelines for the management of Serves Local Anesthetic Toxicity. http://www.aagbi.org/publications/guidelines/docs/latoxicity07.pdf. Downloaded on June 27th 2009

32. Conclusion • IFE is not FDA approved for the treatment of drug toxicity. • Current success with IFE use is limited to animal studies and case reports. • Dose not well defined. Especially infusion after bolus dose • Administer undiluted as 20% fat emulsion • More experience with local anesthetic toxicity • IFE is effective in the management of lipid soluble drug toxicity • Potential antidote of choice for lipid soluble toxins/drugs • Control studies warranted

33. Hydroxocobalamin

34. A 54 – year old woman brought to the hospital from an apartment fire. She had altered mental status, hypotension and evidence of inhalation injury, but no burns. Her carboxyhemoglobin level was 29% and her lactate was 16 mmol/L. She was treated with supplemental and hyperbaric oxygen for CO intoxication. Hydroxocobalamin 5 gm was administered intravenously for presumed cyanide poisoning. 1. How will you prepare hydroxycobalamin for Intravenous administration in this patient 2. What precaution will you take prior to administration of hydoxocobalamin to this patient? 3. What adverse effects will you expect? How will you monitor?

35. 2005 AAPCC report: Cyanide poisoning account for 220 of 2.4 million cases of human poisoning reported to poison centers • The most common source of CN toxicity is smoke inhalation • Estimated to cause 5,000 – 10,000 deaths annually in the US • Mortality from smoke inhalation is about 24 – 31% Smith Dl et al J Trauma 1994;37:655 – 659 Baud FJ et al N Eng J Med 1991;325:1761 – 1766 Silverman SH et al J Trauma 1988;28:171 – 176

38. Adopted from Shepherd G and Velez IL. Ann Pharmacother 2008;42:661 – 669

40. Chromaturia and skin redness: Cescon WD and Juurlink ND. CMAJ. 2009;180(2):180

41. $715.00 $185.00 Adopted from The Ann Pharmacotherapy 2008;42:664 with modification

45. Administration Protocol • Hydroxocobalamin has gain acceptance for the treatment of presumed cyanide poisoning in fire victims in the pre – hospital setting • FDNY – EMS in July 2009 adopted a protocol Patients exposed to smoke: • Hypotension, altered mental status, Coma, seizures • Respiratory arrest, or cardiac arrest • 3 tubes of blood will be drawn before hydroxocobalamin administration

46. Formulary Consideration • Hydroxocobalamin is an FDA approved cyanide antidote with alternative mechanism • Offers straightforward administration with safety profile in patients with smoke inhalation • No methemoglobenemia and hypotension • Offers a more rapid onset of action • Though has higher drug cost, would likely have little impact on hospital’s drug budget • At minimum, stock enough cyanide antidote to treat one patient for up to 24 hours Dart RC et al Ann Emerg. Med 2000;36:126 - 132

47. Conclusions • Hydroxocobalamin has demonstrated efficacy and safety profile in the treatment of patients with cyanide poisoning • Lack of comparative data to support superiority over the 3 – part cyanide antidote • Hydroxocobalamin may be beneficial choice in cases: • Where diagnosis of CN poisoning is uncertain • Where induction of metHb may be detrimental

48. QUESTIONS??