1. Selected Antidotes Jon B Cole, MD Department of Emergency Medicine

2. Objectives Discuss the treatment of carbon monoxide poisoning, including hyperbaric oxygen Discuss the treatment of organophosphate poisoning, including the value of oxime treatment Review old and new treatments of cyanide toxicity Review the indications and uses of some classic antidotes

3. Background Antidote: any substance which can counteract a form of poisoning. Derived from the Greek “anti didonai,” which literally translates as “given against.” Different mechanisms: –Animal antibodies –Enzyme inhibitors –Cofactor –Competitive inhibition –“Universal” antidotes

4. Oxygen (O 2 )

5. The treatment of choice for carbon monoxide (CO) poisoning Normobaric (NBO) vs. Hyperbaric (HBO) HBO also used to treat: –Cyanide (CN) –Hydrogen sulfide (H 2 S) –Carbon tetrachloride (CCl 4 ) –Methylene chloride (Ch 2 Cl 2 ) –Methemoglobinemia –Decompression sickness –Air embolism –Necrotizing fasciitis

6. Carbon Monoxide (CO) Binds hemoglobin with 230-270 times the affinity of oxygen Also binds myoglobin, cytochrome P450, and cytochrome aa 3 –Note: CYP450 is named after the peak absorption of light at 450nm when the enzyme is 50% saturated with CO Transforms the hemoglobin binding curve from a sigmoid to an asymptotic shape

7. Carboxyhemogloin (COHb)

8. Hyperbaric Oxygen (HBO) Physiologic goal is elevation of partial pressure of O 2 Outcome goal is restoration/preservation of normal CNS function as well as reduction in mortality Much controversy exists regarding the benefit of HBO –6 prospective studies have been done to date, all with mixed results 2 of these studies are fairly recent

9. Carboxyhemoblobin – half-life Room Air 3-4 hours 100% NBO 60 min HBO 2.5atm 20 min

10. HBO – Scheinkestel et al (AUS) 191 CO-poisoned patients of different severity High flow O 2 (for 3 or 6 days) vs. HBO (3.0 ATA for 60 minutes daily) Outcome measured was neuropsychiatric testing 1 month after treatment No benefit shown, but…

11. HBO – Scheinkestel et al (AUS) Controversies: –69% of cases were suicide attempts –50% of patients co-ingested EtOH or other drugs –Both the NBO and HBO regimens deviated from standard regimens and were potentially toxic –Many patients had active depression or CNS- affecting drugs on board at 1 month during their neuro-psych testing –Only 46% of the patients completed the follow-up test

12. HBO – Weaver, et al (USA) 152 patients, stratified by age ( 40), time to end of CO exposure, start time of treatment ( 6hrs), hx of LOC. Patients treated 3 times at 6-12 hr intervals in a monoplace chamber Outcomes measured by CO poisoning questionnaires, functional outcome evaluations, neuropsychological test battery given at 2 weeks, 6 weeks, 6 months, and 12 months

13. HBO – Weaver, et al (USA) NBO group did have a higher incidence of cerebellar dysfunction, but this was accounted for HBO group had a lower incidence of cognitive sequelae Risk factors for which HBO therapy was recommended were: –LOC –COHb ≥ 25% –Age 50 ≥ years –Base excess ≤ 2mEq/L Patients without any of these characteristics did not have improved outcomes

14. HBO - Indications Definite: –AMS/Abnormal Neuro Exam –LOC or near-syncope –Coma –Hypotension at any time –MI –“Prolonged” exposure –Pregnancy and COHb ≥ 15% Relative: –Persistent Neurologic Sxs (including HA or dizzy) after 4hrs NBO –Persistent acidosis –Concurrent thermal or chemical burns –Pregnancy regardless of COHb level

15. HBO - Contraindications Paraquat poisoning General HBO contraindications (relative) –Middle ear surgery –Thoracic surgery –Untreated pneumothorax –Seizure disorder –Severe sinusitis

16. HCMC Hyperbaric Chamber

17. HCMC HBO Indications (non-pregnant) LOC COHb ≥ 40% “Serious” toxicity including: –Lethargy, confusion or disorientation on arrival to med facility –Hx of seizures –Focal neuro deficit –Ischemic chest pain –New dysrhythmias or ECG changes –Hypotension COHb ≥ 25% plus: –Hx of CAD –Age ≥ 60 yrs or ≤ 2 years –HGB ≤ 10 –Exposure duration ≥ 2 hours

18. HCMC HBO Indications (pregnant) Patients meeting any of the previous indications COHb ≥ 20% Exposure duration ≥ 5 hrs Any signs of fetal distress

19. HCMC HBO protocol Non-pregnant –100% O 2 by non-rebreather mask until HBO –100% O 2 at 2.4 ATA for 90 min –100% O 2 by non-rebreather until pt without sxs and COHb ≤ 3 –Dispo as appropriate, f/u w/ Neurology in 1 month Pregnant (as above, plus) –Check for fetal distress prior to HBO –L&D fetal monitoring if gestation ≥ 28 weeks –Dispo as appropriate, same Neurology follow-up –F/u w/ OB/GYN in 1 week

20. N-Acetylcysteine (NAC) The mainstay of treatment for acetaminophen (APAP) overdose Other uses include treatment of: –Chloroform –CCl 4 –1,2-dicloropropane –Acrylonitrile –Doxorubicin –Cyclophosphamide –Radiographic contrast exposure

21. APAP metabolism

22. Glutathione (GSH) metabolism NAC Provides a substrate for sulfation Regenerates glutathione (reduced form - GSH) GSH reduces NAPQI, allowing it to be cleared via the kidneys

23. APAP and NAC metabolism NAC allows safe metabolism of the directly hepatotoxic metabolite NAPQI. NAC is itself an antioxidant, which may be more useful in late- presenting overdoses

24. Rumack-Matthew Nomogram Published 1975 Based on a retrospective analysis of previous APAP overdoses and their clinical outcomes Original line at 200mcg/mL, but moved to 150 at urging of FDA 200 still the treatment threshold in Europe

25. NAC – additional indications Consider NAC if patients are on any CYP 2E1 inducers –Isoniazid –Chronic alcohol use/abuse Signs of liver toxicity past 24 hours and still-measurable APAP level Note: pregnancy is NOT a contraindication

26. NAC – oral vs. IV

27. NAC - oral Advantages: –reduced anaphylactoid reaction risk –Safer in asthmatics Disadvantages: –Horrible smell –Vomiting common (may need antiemetics) –Dosing is over 72 hours 140mg/kg load 70mg/kg dose q 4 hrs thereafter for 17 does

28. IV NAC - Acetadote ®

29. Advantages: –Shorter treatment course – 21 hours 150mg/kg loading dose over 1 hr (instead of 15 min) 50mg/kg in 500mL D5W over 4 hrs 100mg/kg in 1000mL D5W over 16 hrs –New dosing guidelines for < 40kg patients now available –Decreased GI effects –Actually studied in hepatic failure Disadvantages: –Increased anaphylactoid reactions –More costly (debatable) –Difficult Peds dosing Initial reports of hyponatremia from increased water infusion

30. Allergic reactions – What to do Stop the IV infusion immediately Treat accordingly –Diphenhydramine, steroids, epi if indicated Once the reaction resolves, infusion can be re-started If the reaction persists or worsens, stop the IV infusion and either switch to oral or re-evaluate the need for NAC –Oral has been proven very safe in patients who have had severe reactions to the IV perparation

31. Physostigmine (Antilirium ® ) The antidote for anti-cholinergic toxicity A carbamate that reversibly inhibitis cholinesterases in both the CNS and PNS Derived from the plant Physostigma venenosum Balfour, from Nigeria

32. Physostigmine Originally used as a miotic agent to treat glaucoma, and in the treatment of myasthenia gravis Also used as an antidote to atropine toxicity, and as an insecticide Structure is tertiary amine (other “stigmines” are quaternary), which allows better CNS penetration.

33. Tertiary vs. Quaternary Amines Physostigmine Uncharged Neostigmine Charged

34. Physostigmine Available only as an IV preparation Dose: 1-2mg infused over at least 5 min (0.02mg/kg in peds). Onset of action is within minutes Dose can be repeated q 10-15 min T1/2 is 16 minutes, but duration of action is usually much longer

35. Physostigmine and TCA OD Physostigmine was used often in the 1970s to treat undifferentiated delerium Case report by Pentel in 1980 re: 2 patients who suffered asystole after receiving physostigmine for TCA overdoses Since then the antidote has greatly fallen out of favor

36. Physostigmine - Indications Peripheral or Central anti-cholinergic manifestations without evidence of QRS or QTc prolongation, such as: –Agitation –Hypertheria –Hallucinations –Delerium –Seizures –coma The patient to use this in is a known non-TCA anti-cholinergic overdose

37. Physostigmine - contraindications Definite contraindications: –Suspicion of TCA ingestion –Widened QRS on ECG Relative contraindications: –History of asthma –Concomitant use of succinylcholine –Parkinsonism –AV block Beware “evidence based medicine” such as uptodate.com

38. Opioid Antagonists Primarily μ-antagonists, some secondary antagonism of κ and δ receptors. 3 options available: –naloxone (Narcan ® ) –nalmefene (Revex ® ) –naltrexone (Revia ® ) The primary difference between the three drugs is their duration of action

39. Opioid Antagonists Naloxone –Duration of action 1-2 hours –Can be started as a drip –Re-assess for respiratory distress Nalmefene –Duration of action up to 4 hours –More expensive Naltrexone –Duration of action up to 24 hours –Oral preparation only

40. Opioid Antagonists Used primarily in the treatment of opioid overdose, though naloxone is used to treat other overdoses such as: –Clonidine –Ethanol –Benzodiazepines –Valproic acid –captopril No major contraindications

41. Opioid Antagonists - Structure AgonistAntagonist

42. Naloxone Dosing “Waking up” vs. withdrawal – different approaches Usual dosing is to start low and titrate up –0.4mg, then 2mg, then 10mg –If no response, consider another cause of coma Remember, naloxone can be given via the endotraheal tube, but dosing should be 2- 3x.

43. Flumazenil (Romazicon ® ) A competetive benzodiazepine receptor antagonist. Unlike naloxone, flumazenil is NOT indicated as part of the “coma cocktail,” as it has potentially serious side-effects and minimal benefit

44. Flumazenil Flumazenil precipitates seizures in benzodiazepine dependent patients, and in patients with underlying seizure disorders –The “zero setpoint” of intrinsic CNS activity may be influenced by GABA activity and chronic benzo use Flumazenil can also unmask dysrhythmias in patients who co-ingest pro-arryhthmic drugs

45. Flumazenil - Indications Known benzo ingestion in benzo-naïve patients, e.g. –Iatrogenic exposure –Toddler ingestion –Paradoxic benzo response Postoperative or postprocedure sedation reversal CNS depression from hepatic encephalopathy

46. Flumazenil - dosing Start with 0.2mg IV over 30 seconds (0.01mg/kg in children) If no response, then 0.3mg over 30 seconds If still no response give 0.5mg every 30 seconds up to 3 mg

47. Atropine A competetive anti-muscarinic drug that acts both centrally and peripherally Derived from the plant Atropa belladonna Similar to physostigmine it has a teritiary amine structure, whereas other anti-muscarinic drugs such as glycopyrrolate are quaternary amines

48. Tertiary vs. Quaternary Amines AtropineGlycopyrrolate

49. Atropine - Indications Organophosphate poisoning “Nerve Gases” Carbamate poisoning Bradycardia from: –Beta blockers –Calcium antagonists –Digitalis –Other AV node-blockers

50. Atropine - Contraindications All are relative –Angle-closure glaucoma –Myasthenia gravis –Obstructive uropathy –Obstructive GI diseases (severe ulcerative colitis) –Hypertension –Thyrotoxicosis –Tachyarrhythmias –CAD –Valvular disease

51. Atropine Dosing in Organophosphates Based on work by Eddelstein, et al, J Clin Tox, 2004 Starting dose is 0.5-2mg, then doubling every 5 minutes until “endpoint” is achieved –Pediatric starting dose is 0.02mg/kg Goal is “atropinization” –Clear chest on auscultation –Increased heart rate > 80 Each poisoned patient may need as much as 75mg of atropine, so be prepared to mobilize stores

52. Pralidoxime (2-PAM ® or Protopam ® ) Used in the treatment of organophosphate (OP) poisoning OPs exert their effects by phosphrylating cholinesterases, inactivating them Cholinestereases break down acetylcholine (ACh), so ACh builds up in synapses and causes a cholinergic or muscarinic crisis

53. Pralidoxime Quaternary oxime

54. Pralidoxime - mechanism Bound (inactive) undergo one of three processes: –Endogenous hydrolysis and recovery (as with carbamates, such as physostigmine) –Reactivation by a strong nucleophile (e.g. 2-PAM) –“Aging,” which involves biochemical changes to the enzyme that result in permenant dysfunction Oximes work to prevent aging by exerting a nucleophilic attack on the phosphate moiety, releasing it from the enzyme and preventing aging

55. Pralidoxime Believed to work synergistically with atropine Can be used in severe carbamate poisonings Some evidence the drug should be used within 48 hrs – by this time aging may be inevitable A mainstay of OP poisoning treatment, but…

56. Pralidoxime – benefit? There is now evidence that oximes may not only not improve mortality, they may be harmful. –Buckley, et al (2005) Cochrane Database Two published RCTs, one abstract RCT Insufficient evidence for harm or benefit of oximes –Peter, et al (2006) Crit Care Med Two published RCTs, 5 controlled trials Oximes either ineffective or harmful –Rahimi, et al (2006) Human Exp Toxicol Six clinical trials Oximes are not effective and can be dangerous

57. Pralidoxime For now, it is the standard of care Always use with atropine Field Dosing –600mg IM from the autoinjector, up to 3 doses Hospital Dosing is –1-2g IV over 15-30min as initial dose 25-50mg/kg in children –Continuous infusion of 200-500mg/hr thereafter 5-10mg/kg in children

58. The Mark I Nerve Agent Antidote Kit 600mg IM of pralidoxime 2mg IM of atropine

59. Treatment of cyanide (CN) CN is toxic because it binds the ferric (Fe 3+ ) ion in cytochrome oxidase, uncoupling oxidative phosphorylation and causing chemical asphyxia. Treatment involves –creating other sources of Fe 3+, –inducing the enzyme that clears CN, and –providing another oxidized ion (Co + ) for the CN to bind with

60. Nitrites Nitrites (-NO 2 ) oxidize the iron in hemoglobin from Fe 2+ to Fe 3+ to create methemoglobin Since CN reversibly binds the Fe3+ in cytochrome oxidase, it now has a new competetive pool of Fe3+ to bind

61. Amyl Nitrite A volatile (and flammable) gas Comes in 0.3mL ampules Administered by breaking open the ampule and holding it in front of the patient’s mouth for 15 seconds on, then 15 seconds off, etc. Should be discontinued as soon as an IV can be established This is a stop-gap solution

62. Sodium Nitrite Comes in a 10mL vial, 300mg Administered IV at 2.5-5mg/min Should be followed immediately with IV sodium thisulfate

63. Nitrites Indications –Symptomatic cyanide poisoning –Hydrogen sulfide (H 2 S) poisoning < 30 min ago Contraindications –Significant (>40%) pre-existing methemoglobinemia –Severe hypotension –Concomitant CO poisoning/smoke inhalation

64. Sodium Thiosulfate (Na 2 S 2 O 3 ) This relatively non-toxic CN antidote works to regenerate the mitochondrial enzyme rhodanese. Rhodanese metabolizes CN to thiocyante (SCN - ) by using a unique sulfur bond on the enzyme known as a sulfane group This is the only type of sulfur that reacts with CN

65. Sodium Thiosulfate (Na2S2O3) Comes in 50mL bottles containing 12.5 Given IV as a bolus or over 10-30 min depending on severity of illness No significant contraindications

66. Nitrites and Thiosulfate - Summary

67. Taylor Pharmaceuticals Cyanide Antidote Kit 12 ampules of amyl nitrite 2 ampules of sodium nitrite 2 vials of sodium thiosulfate Cost: $317.18 each

68. hydroxycobalamin (Cyanokit ® ) Hydroxycobalamin is a direct precursor to cyanocobalamin (a member of the vitamin B12 family) FDA approved in 2007 Very safe

69. Hydroxycobalamin - metabolism HydroxycobalaminCyanocobalamin

70. Hydroxycobalamin Dosing: –5g IV given over 15 minutes Side effects: –Turns body fluids bright red within minutes Interactions: –Do not administer in the same line as sodium thiosulfate, as they will bind each other rendering them both ineffective

71. References Pentel, P, et al, “Asystole Complicating Physostigmine Treatment of Tricyclic Antidepressant Overdose,” Ann Emerg Med, Nov 1980, pp 588-590 Cocuzza, et al, “Inappropriate Use of Physostigmine in TCA Toxicity: An Online Medical Reference May Be Partially Responsible,” Clinical Toxicology, Vol 46, No 7, Aug 2008 Goldfrank, L, et al, “Goldfrank’s Toxicologic Emergencies,” McGraw-Hill, Mar 2006, pp 1- 22, 544-549, 614-619, 794-797, 1112-1117, 1513-1518, 1519-1522, 1705-1711, 1725- 1727, 1728-1730, 1731-1733 Dart, RC, “Medical Toxicology,” Ch. 5, “Antidote Stocking,” Lippincott, Wilkens, & William, December, 2003, pp 159-163 Weaver, LK, et al, “Hyperbaric Oxygen for Acute Carbon Monoxide Poisoning,” NEJM, Oct. 3, 2002, pp 1057-1067 Scheinkestel, CD, et al, “Hyperbaric or normobaric oxygen for acute carbon monoxide poisoning: a randomised controlled clinical trial,” Medical Journal of Australia, 1999, 170: 203-210 HCMC Guidelines for Treatment of Carbon Monoxide Poisoning, current as of August 2008 Olson, KR, et al, “Poisoning & Drug Overdose,” Lange Medical Books/McGraw-Hill, 2004, pp406-519 Cyanokit manufacturer’s package insert, current as of August 2008 Acetadote manufacturer’s package insert, current as of August 2008