Acetaminophen and Salicylates Toxicity and Management

1
Acetaminophen and SalicylatesToxicity and
Management

• Joseph Rella, MD
• Emergency Medicine
• NJMS

2
Substances most frequently involved in Human
exposures

• 284,906
• 214,780
• 214,091
• 141,150
• 120,752

• Analgesics
• Cosmetics and personal care products
• Cleaning Substances
• Sedative-Hypnotics-Antipsychotics
• Foreign bodies

Bronstein AC, Spyker DA, Cantilena LR, et al 2006
Annual Report of the American Association of
Poison Control Centers Toxic Exposure
Surveillance System. ClinToxicol 200745815-917
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 200745815-917
4
American Association of Poison Control Centers
2006 Annual Report

• In the group Analgesics, Acetaminophen and
  Salicylate make up 40 of the cases reported.

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AcetaminophenN acetyl p aminophenol (APAP)
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Acetaminophen

• First synthesized and used in the late 1800s
• Rediscovered in 1950
• A metabolite of phenacetin, it was not widely
  accepted in the medical community until the
  1970s

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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

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Metabolism
N-acetylparabenzoquinoneimine
Acetaminophen glutathione conjugate
9
Overdose!
UDP-glucuronosyl- transferase
Urine
Saturated
lt5
Acetaminophen
Phenosulfotransferase
CytoP450
39
Glutathione (GSH)
Acetaminophen glutathione conjugate
Acetaminophen sulfate
NAPQI
Binding to cellular proteins leading to hepatic
and renal injury
N-acetylparabenzoquinoneimine
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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

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Organ Toxicity

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

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Anatomy of a Liver Lobule
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Normal Liver
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(No Transcript)
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Cirrhosis
Centilobular necrosis
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Most people took less than they say they did,
except for those who took more.
Number of people
amount
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Clinical evidence of toxicity

• Phase 1 0-24 hours
• Nausea, vomiting, nothing
• Phase 2 24-72 hours
• RUQ pain, elevated liver enzymes, prolonged PT
• Phase 3 72-96 hours
• Hepatic necrosis, encephalopathy, coagulopathy,
  ATN
• Phase 4 4 days- 2 weeks
• If damage is not irreversible, complete
  resolution of hepatic dysfunction will occur

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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

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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

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Rumack-Matthew Nomogram
500
200
Potential for Toxicity
150
100
50
Toxicity Unlikely
APAP concentration mcg/mL
10
4
8
16
12
20
24
Time after ingestion
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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
  19883191557-1562
• 11,000 patients enrolled
• 2,200 patients treated
• 8 hour treatment window

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Laboratory predictors of poor prognosisThe
Kings College Criteria

• pH lt 7.30
• Or
• PT gt 100sec, Creatinine gt 3.4 mg/dL, grade III
  Encephalopathy
• ( vitamin k vs. FFP)
• PPV 98 NPV82

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Laboratory predictors of poor prognosisThe
Clichy Criteria

• Factor V lt 50 of normal
• Age
• Absence of HBsAg
• ? fetoprotein level
• PPV90 NPV94

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Laboratory predictors of poor prognosisSerum
Phosphorus
Chung PY, Sitrin MD, Te HS. Serum phosphorus
level predict clinical outcome in fulminant
hepatic failure. Liver Transplantation.
20039248-253
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GI Decontamination

• Very rapid GI absorption
• Activated Charcoal
• Very early presentation
• Co-ingestants
• Adsorbs to NAC

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N-Acetylcysteine therapy

• Prevents toxicity by limiting NAPQI formation
• Increases capacity to detoxify formed NAPQI

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NAC-Good for what ails you
NAC
NAC
NAC
NAC
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Late NAC Therapy

• Decreased hepatotoxicity when treatment begins
  16-24 hours post ingestion
• Smilkstein, Knapp, Kulig, Rumack.
  N-Acetylcysteine in the treatment of
  acetaminophen overdose. N Engl J Med
  19893201418
• 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
  19913031026-1029

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Other Benefits of NAC

• Improved oxygen delivery and utilization in
  extrahepatic organs
• Helps preserve cerebral blood flow
• Possibly due to mediation of microvascular tone

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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

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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

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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

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Non-acute ingestions

• Hepatotoxicity is rare
• Usually seen in pediatric population
• Poor label-reading
• Mom Dad

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Case Examples

• Acute ingestion 4-hour level 155mcg/mL
• Acute ingestion 4-hour level 149mcg/mL
• Acute ingestion 1-hour presentation
• Acute ingestion 6-hour presentation
• Unknown time of ingestion
• Unknown time of ingestion, AST 2500

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Salicylates
Acetyl salicylic acid
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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
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Pharmacokinetics

• pKa of 3.5
• Peak serum levels in 30 minutes
• Absorbed well in stomach and intestine

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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

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Toxicity

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

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Metabolism
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Overdose!
Methyl salicylate
Acetyl Salicylic acid
2.5
More ASA Absorbed Decreased Protein binding
Urine
pH
Salicylic acid
SATURATED
Salicyluric acid
Gentisic acid
Ether glucuronide
Ester glucuronide
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Normal Energy Generation
Krebs Cycle
Glycolysis
Glucose
Pyruvate
Pyruvate decarboxylase
CO2
Oxidative Phosphorelation
NADH2
H2O
ATP
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Salicylate Uncoupling
ATP
Krebs Cycle
Glycolysis
Glucose
Pyruvate
Pyruvate decarboxylase
CO2
Lactate
Oxidative Phosphorelation
NADH2
H2O
SALICYLATES
ATP
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MUDPILES

• Methanol
• Uremia
• DKA, SKA, AKA
• Paraldehyde
• INH, Iron, Infection

• Lactate
• Ethylene glycol
• Salicylates

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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 gt 100mg/dL

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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

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Rapid ASA Confirmation
FeCl2
Salicylic Acid
(Purple colored complex)
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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)

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ABG Describes the Toxicity

• Early pure respiratory alkalosis
• 7.50 / 30 7.60 / 20
• Later add metabolic acidosis
• 7.47 / 25
• Late severe toxicity
• 7.40 / 15

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Urinary Alkalinization

• Acidemia facilitates transfer of ASA into tissue
• Acetazolamide creates alkyluria AND metabolic
  acidosis
• NaBicarbonate increases urinary elimination
  10-20 times
• Bolus 1-2 mEq/kg followed by 3 amps
• (132-150mEq) in 1 L D5W at 1.5-2 times
  maintenance
• Urine pH 7.5-8.0
• Serum pH not to exceed 7.55

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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 197141475-484
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Effects of Urinary Alkalinization
Prior to Alkalinization
Temple AR. Acute and chronic effects of aspirin
toxicity and their treatment. Arch Intern Med
1981141367
55
Effects of Urinary Alkalinization
After Alkalinization
Temple AR. Acute and chronic effects of aspirin
toxicity and their treatment. Arch Intern Med
1981141367
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

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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