1. Acetaminophen and Salicylates Toxicity and Management
Joseph Rella, MD
Emergency Medicine
NJMS

2. Substances most frequently involved in Human exposures
Analgesics
Cosmetics and personal care products
Cleaning Substances
Sedative-Hypnotics-Antipsychotics
Foreign bodies
284,906
214,780
214,091
141,150
120,752
Bronstein AC, Spyker DA, Cantilena LR, et al 2006 Annual Report of the American Association of
Poison Control Centers Toxic Exposure Surveillance System. ClinToxicol 2007;45:

3. Categories with the largest number of deaths
Sedatives-Hypnotics-Antipsychotics
Opioids
Cardiovascular drugs
Antidepressants
Stimulants and street drugs
Acetaminophen (alone or combo)
382
307
252
210
203
352
Bronstein AC, Spyker DA, Cantilena LR, et al 2006 Annual Report of the American Association of
Poison Control Centers Toxic Exposure Surveillance System. ClinToxicol 2007;45:

4. American Association of Poison Control Centers 2006 Annual Report
In the group Analgesics, Acetaminophen and Salicylate make up 40% of the cases reported.

5. Acetaminophen N – acetyl – p – aminophenol (APAP)

6. Acetaminophen First synthesized and used in the late 1800’s
“Rediscovered” in 1950
A metabolite of phenacetin, it was not widely accepted in the medical community until the 1970’s

7. Got Acetaminophen?
Caplets: Arthritis Foundation Pain Reliever Aspirin Free Aspirin Free Pain Relief Aspirin Free Anacid Maximum Strength Atasol Atasol Forte Genapap Extra Strength Genebs Extra Strength Caplets Panadol Panadol Junior Strength Tapanol Extra Strength Tylenol Arthritis Extended Relief Tylenol Caplets Capsules: Dapacin Meda Cap Elixir: Aceta Genapap Children's Mapap Children's Oraphen-PD Ridenol Silapap Children's Tylenol Children's Gelcaps: Aspirin Free Anacid Maximum Strength Tapanol Extra Strength Tylenol Extra Strength Oral Liquid/Syrup: Atasol Children's Acetaminophen Elixir Drops Halenol Children's Panadol Children's Pediatrix Tempra Tempra 2 Syrup Tempra Children's Syrup Tylenol Extra Strength Oral Solution: Acetaminophen Drops Apacet Atasol Children's Acetaminophen Oral Solution Genapap Infants' Drops Mapap Infant Drops Panadol Infants' Drops Pediatrix PMS-Acetaminophen Silapap Infants Tempra 1 Tylenol Infants' Drops Uni-Ace Oral Suspension: Tylenol Children's Suspension Tylenol Infants' Suspension Sprinkle Capsules: Feverall Children's Feverall Junior Strength Suppositories: Abenol 120, 325, 650 mg Acephen Acetaminophen Uniserts Children's Feverall Infant's Feverall Junior Strength Feverall Neopap Tablets: Aceta A.F. Anacin A.F. Anacin Extra Strength Apo-Acetaminophen Aspirin Free Pain Relief Aspirin Free Anacin Maximum Strength Atasol Atasol Forte Extra Strength Acetaminophen Fem-Etts Genapap Genapap Extra Strength Genebs Genebs Extra Strength Mapap Regular Strength Mapap Extra Strength Maranox Meda Tab Panadol Redutemp Regular Strength Acetaminophen Tapanol Regular Strength Tapanol Extra Strength Tempra Tylenol Regular Strength Tylenol Extra Strength Tylenol Junior Strength Tylenol Tablets 325 mg, 500 mg Tablets, Chewable: Apacet Children's Chewable Acetaminophen Children's Genapap Children's Panadol Children's Tylenol Tempra Tempra 3 Tylenol Chewable Tablets Fruit Tylenol Junior Strength Chewable Tablets Fruit (OTC) Acetaminophen, buffered Acetaminophen, buffered (Bromo Seltzer) Acetaminophen, buffered

8. Metabolism Urine 5-15% Glutathione (GSH) <5% 50% 40% Acetaminophen
Acetaminophen glucuronide
Urine
Acetaminophen
Acetaminophen sulfate
Phenosulfotransferase
UDP-glucuronosyl-
transferase
50%
40%
<5%
5-15%
CytoP450
Glutathione (GSH)
N-acetylparabenzoquinoneimine
Acetaminophen glutathione conjugate

9. Overdose! Saturated Urine NAPQI Binding to cellular proteins
UDP-glucuronosyl-
transferase
Urine
Saturated
<5%
Acetaminophen
Phenosulfotransferase
CytoP450
39%
Glutathione (GSH)
Acetaminophen glutathione conjugate
Acetaminophen sulfate
NAPQI
Binding to cellular proteins
leading to hepatic and renal
injury
N-acetylparabenzoquinoneimine

10. NAPQI Toxicity A highly reactive electrophile
Covalently binds to and arylates critical cell proteins leading to cell death
This process is not inevitable
This process may be prevented, interrupted, and reversed

11. Organ Toxicity NAPQI-derived Multiorgan failure Poorly defined
Liver – begins in zone 3 (centrilobular)
Renal – Acute Tubular Necrosis
Multiorgan failure
Heart, kidney
Poorly defined
Brain
Pancreas

12. Anatomy of a Liver Lobule

13. Normal Liver

15. Cirrhosis
Centilobular necrosis

16. Most people took less than they say they did, except for those who took more.
Number of people
amount

17. Clinical evidence of toxicity
Phase 1 – 0-24 hours
Nausea, vomiting, nothing
Phase 2 – hours
RUQ pain, elevated liver enzymes, prolonged PT
Phase 3 – hours
Hepatic necrosis, encephalopathy, coagulopathy, ATN
Phase 4 – 4 days- 2 weeks
If damage is not irreversible, complete resolution of hepatic dysfunction will occur

18. Toxic Dose
Acute overdose is usually considered to be a single ingestion
Generally, 7.5 gm in an adult or 150 mg/kg in a child are the lowest threshold capable of toxicity

19. Risk Assessment Fatalities are relatively uncommon
The overwhelming majority of APAP exposures result in no toxicity
The antidote is very safe

20. Risk Assessment Plasma GSH is not related to hepatic GSH availability
Protein adducts (NAPQI bound to hepatic proteins) are measurable, but follow hepatic necrosis

21. Rumack-Matthew Nomogram
500
200
Potential
for Toxicity
150
100 50
Toxicity
Unlikely
APAP concentration mcg/mL 10 4 8 12 16 20 24
Time after ingestion

22. Validation of the Nomogram
Smilkstein, Knapp, Kulig, Rumack. Efficacy of oral N-Acetylcysteine in the treatment of acetaminophen overdose: Analysis of the national multicenter study. N Engl J Med 1988;319:
11,000 patients enrolled
2,200 patients treated
8 hour treatment window

23. Laboratory predictors of poor prognosis: The King’s College Criteria
pH < 7.30 Or
PT > 100sec, Creatinine > 3.4 mg/dL, grade III+ Encephalopathy
( vitamin k vs. FFP)
PPV= 98% NPV=82%

24. Laboratory predictors of poor prognosis: The Clichy Criteria
Factor V < 50% of normal
Age
Absence of HBsAg
Α fetoprotein level
PPV=90% NPV=94%

25. Laboratory predictors of poor prognosis: Serum Phosphorus
Chung PY, Sitrin MD, Te HS. Serum phosphorus level predict clinical outcome in fulminant hepatic failure.
Liver Transplantation. 2003;9:

26. GI Decontamination Very rapid GI absorption Activated Charcoal
Very early presentation
Co-ingestants
Adsorbs to NAC

27. N-Acetylcysteine therapy
Prevents toxicity by limiting NAPQI formation
Increases capacity to detoxify formed NAPQI

28. NAC-Good for what ails you
Acetaminophen glucuronide
Urine
Acetaminophen
Acetaminophen sulfate
Phenosulfotransferase
UDP-glucuronosyl-
transferase
50%
40%
<5%
5-15%
CytoP450
Glutathione (GSH)
NAC
NAC
NAC
NAC

29. Late NAC Therapy
Decreased hepatotoxicity when treatment begins hours post ingestion
Smilkstein, Knapp, Kulig, Rumack. N-Acetylcysteine in the treatment of acetaminophen overdose. N Engl J Med 1989;320:1418
IV NAC begun after onset of fulminant hepatic failure decreased need for vasopressors, and decreased incidence of cerebral edema and death
Keays, Harrison, Wendon, et al. Intravenous acetylcysteine in paracetamol induced fulminant hepatic failure: A prospective trial. Br Med J 1991;303:

30. Other Benefits of NAC
Improved oxygen delivery and utilization in extrahepatic organs
Helps preserve cerebral blood flow
Possibly due to mediation of microvascular tone

31. Treat everyone the Same?
Only the 17dose oral NAC regimen has been extensively studied – in the US
140 mg/kg loading dose – 17 doses 70 mg/kg po
Shorter courses of therapy
Longer courses of therapy

32. What about IV NAC? Pro Con No vomiting Consistent delivery
Only route studied for fulminant hepatic failure
Pregnancy?
Anaphylactoid response
No first-pass effect
More costly
No guarantee of sterility or pyrogen free

33. The long-awaited… 150 mg/kg in 200mL D5W over 15min
50mg/kg in 500mL D5W over 4 hours
100 mg/kg in 1L D5W over 16 hours

34. Non-acute ingestions Hepatotoxicity is rare
Usually seen in pediatric population
Poor label-reading
Mom & Dad…

35. Case Examples Acute ingestion 4-hour level 155mcg/mL
Acute ingestion 1-hour presentation
Acute ingestion 6-hour presentation
Unknown time of ingestion
Unknown time of ingestion, AST 2500

36. Salicylates
Acetyl salicylic acid

37. Got Salicylates?
Apo-Asa   Asaphen   Aspergum Aspirin Aspirin Regimen Bayer 81 mg with Calcium Bayer Children's Aspirin Easprin Ecotrin Caplets and Tablets Ecotrin Maximum Strength Caplets and Tablets Empirin Entrophen   Excedrin Geltabs Genprin Genuine Bayer Aspirin Caplets and Tablets Halfprin 8-Hour Bayer Timed-Release Caplets Maximum Bayer Aspirin Caplets and Tablets MSD Enteric Coated ASA   Norwich Extra Strength Novasen   St. Joseph Adult Chewable Aspirin Therapy Bayer Caplets ZOR-prin (OTC) (Easprin and ZOR-prin are Rx) Acetylsalicylic acid, buffered Acetylsalicylic acid, buffered (Ascriptin Regular Strength, Bufferin) Acetylsalicylic acid, buffered Alka-Seltzer with Aspirin Alka-Seltzer with Aspirin (flavored) Alka-Seltzer Extra Strength with Aspirin Arthritis Pain Formula Ascriptin Regular Strength Ascriptin A/D Bayer Buffered Buffered Aspirin Bufferin Buffex Cama Arthritis Pain Reliever Magnaprin Magnaprin Arthritis Strength Captabs Tri-Buffered Bufferin Caplets and Tablets

38. Pharmacokinetics pKa of 3.5 Peak serum levels in 30 minutes
Absorbed well in stomach and intestine

39. Toxicokinetics Above 30 mg/dL
Delayed absorption from pylorospasm, bezoar formation
Peak serum levels 4 – 6 or more hours
At toxic levels, elimination routes are saturated
Decreased fraction protein bound*

40. Toxicity Primary respiratory stimulant Tinnitus
Gastrointestinal upset and pylorospasm
Diaphoresis
Mental status changes
Acute Lung Injury
Increased brain utilization of glucose
Metabolic acidosis

41. Metabolism 2.5% Absorbed, Protein Urine binding pH Salicyluric acid
Ether glucuronide
Ester glucuronide
Gentisic acid
Acetyl
Salicylic
acid
Methyl
salicylate
2.5% pH
Urine
Absorbed, Protein
binding
Salicylic acid

42. Overdose! SATURATED 2.5% More ASA Absorbed Urine Decreased Protein pH
Methyl
salicylate
Acetyl
Salicylic
acid
2.5%
More ASA Absorbed
Decreased Protein
binding
Urine pH
Salicylic acid
SATURATED
Salicyluric acid
Ether glucuronide
Ester glucuronide
Gentisic acid

43. Normal Energy Generation
Kreb’s
Cycle
Glycolysis
Glucose
Pyruvate
Pyruvate
decarboxylase
CO2
Oxidative Phosphorelation
H2O
NADH2
ATP

44. Salicylate Uncoupling
ATP
Kreb’s
Cycle
Glucose
Glycolysis
Pyruvate
Pyruvate
decarboxylase
CO2
Lactate
Oxidative Phosphorelation
H2O
NADH2
SALICYLATES
ATP

45. MUDPILES Methanol Uremia DKA, SKA, AKA Paraldehyde
INH, Iron, Infection
Lactate
Ethylene glycol
Salicylates

46. Does Serum Level Correlate with Acute Toxicity?
Serum levels not tissue levels
Done nomogram – 1960
Methylsalicylate – rapid deterioration
Follow levels closely with: arterial pH, clinical condition
Serum levels > 100mg/dL

47. Chronic Salicylism Most common in the elderly-unintentional
May include any sign consistent with acute toxicity
May also present as:
Delerium
Dementia
Encephalopathy of unknown origin
Congestive heart failure

48. Rapid ASA Confirmation
+ FeCl2
Salicylic Acid
(Purple colored complex)

49. Management Decontamination Blood work
ABG
ASA level – mg/dL
Electrolytes – K+, BUN/Cr
Fluid resuscitation - a return to euvolemia
Electrolyte repletion
An appropriate cry for help?

50. GI Decontamination Activated Charcoal
Multiple Dose Activated Charcoal (MDAC)
Whole Bowel Irrigation (enteric coated)

51. ABG Describes the Toxicity
Early – pure respiratory alkalosis
7.50 / / 20
Later – add metabolic acidosis
7.47 / 25
Late – severe toxicity
7.40 / 15

52. Urinary Alkalinization
Acidemia facilitates transfer of ASA into tissue
Acetazolamide creates alkyluria AND metabolic acidosis
NaBicarbonate – increases urinary elimination times
Bolus 1-2 mEq/kg followed by 3 amps
( mEq) in 1 L D5W at times maintenance
Urine pH
Serum pH not to exceed 7.55

53. Urinary Alkalinization
Alkalinizing urine from pH 5-8 increases renal elimination of ASA from 1.3 mL/min to 100 mL/min
Serum half-life decreases from 48 hours to 6 hours
Morgan AG, Polak A. The excretion of salicylate in salicylate poisoning. Clin Sci 1971;41:

54. Effects of Urinary Alkalinization
Prior to Alkalinization
Tissues pH 6.8
Plasma pH 7.1
Urine pH 6.5 HA
H+ + A-
Temple AR. Acute and chronic effects of aspirin toxicity and their treatment. Arch Intern Med 1981;141:367

55. Effects of Urinary Alkalinization
After Alkalinization
Tissues pH 6.8
Plasma pH 7.4
Urine pH 8 HA
H+ + A-
Temple AR. Acute and chronic effects of aspirin toxicity and their treatment. Arch Intern Med 1981;141:367

56. Problems with Alkalinization
Pre-existing Hypokalemia
Hypokalemia from serum alkalinization
Collecting tubule will excrete H+
Urine pH remains low
Elimination remains limited
CHF
Poor Renal Function

57. Extracorporeal Removal
Very ill with salicylate poisoning
Very high level
Severe fluid and electrolyte disturbance
Unable to eliminate salicylates
Hemoperfusion has better clearance
Hemodialysis allows for fluid, electrolyte, acid-base correction