Acetaminophen
and
Salicylates
Toxicity and Management
Joseph Rella, MD
Emergency Medicine
NJMS
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;45:815-917
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;45:815-917
American Association of Poison
Control Centers 2006 Annual Report
In the group Analgesics, Acetaminophen and
Salicylate make up 40% of the cases
reported.
Acetaminophen
N – acetyl – p – aminophenol (APAP)
O
H
C
N
OH
CH 3
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
Got Acetaminophen?
Caplets: Arthritis Foundation Pain Reliever Aspirin Free Aspirin Free Pain Relief Aspirin Free Anacid Maximum Strength
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Children's Mapap Children's Oraphen-PD Ridenol Silapap Children's Tylenol Children's Gelcaps: Aspirin Free Anacid
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Elixir Drops Halenol Children's Panadol Children's Pediatrix Tempra Tempra 2 Syrup Tempra Children's Syrup Tylenol
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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
O
H
Urine
C
N
Metabolism
O
UDP-glucuronosyltransferase
CH 3
H
N
CH 3
50%
<5%
Acetaminophen
O C 6H 8O6
CytoP450
-
Acetaminophen glucuronide
OH
O
H
5-15%
C
N
CH 3
O
O
C
C
N
C
N
CH3
CH3
O SO3
-
Acetaminophen sulfate
Glutathione (GSH)
SG
OH
O
N-acetylparabenzoquinoneimine
Acetaminophen glutathione conjugate
O
H
Urine
C
N
Overdose!
O
UDP-glucuronosyltransferase
CH 3
H
C
N
CH 3
<5%
Acetaminophen
O C 6H 8O6
OH
O
O
H
C
CytoP450
N
CH3
C
N
CH 3
SG
O
OH
C
N
-
CH3
Acetaminophen glutathione conjugate
O SO3
-
Acetaminophen sulfate
NAPQI
O
N-acetylparabenzoquinoneimine
Binding to cellular proteins
leading to hepatic and renal
injury
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
Organ Toxicity
• NAPQI-derived
– Liver – begins in zone 3 (centrilobular)
– Renal – Acute Tubular Necrosis
• Multiorgan failure
– Heart, kidney
• Poorly defined
– Brain
– Pancreas
Anatomy of a Liver Lobule
Normal Liver
Cirrhosis
Centilobular necrosis
Number of people
Most people took less than they
say they did, except for those
who took more.
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
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
Risk Assessment
• Fatalities are relatively uncommon
• The overwhelming majority of APAP
exposures result in no toxicity
• The antidote is very safe
Risk Assessment
• Plasma GSH is not related to hepatic GSH
availability
• Protein adducts (NAPQI bound to hepatic
proteins) are measurable, but follow hepatic
necrosis
Rumack-Matthew Nomogram
500
200
Potential
for Toxicity
APAP concentration mcg/mL
150
100
50
Toxicity
Unlikely
10
4
8
12
Time after ingestion
16
20
24
Validation of the Nomogram
• Smilkstein, Knapp, Kulig, Rumack. Efficacy of oral NAcetylcysteine in the treatment of acetaminophen
overdose: Analysis of the national multicenter study.
N Engl J Med 1988;319:1557-1562
• 11,000 patients enrolled
• 2,200 patients treated
• 8 hour treatment window
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%
Laboratory predictors of poor prognosis:
The Clichy Criteria
•
•
•
•
Factor V < 50% of normal
Age
Absence of HBsAg
Α fetoprotein level
PPV=90%
NPV=94%
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;9:248-253
GI Decontamination
• Very rapid GI absorption
• Activated Charcoal
– Very early presentation
– Co-ingestants
– Adsorbs to NAC
N-Acetylcysteine therapy
• Prevents toxicity by limiting NAPQI
formation
• Increases capacity to detoxify formed
NAPQI
NAC-Good for what ails you
O
H
Urine
O
C
UDP-glucuronosyltransferase
CH 3
N
H
CH 3
O C 6H 8O6
CytoP450
-
Acetaminophen glucuronide
OH
NAC
O
H
5-15%
C
N
CH 3
O
O
C
C
N
N
50%
<5%
Acetaminophen
NAC
C
CH3
NAC
N
CH3
O SO3
-
Acetaminophen sulfate
Glutathione (GSH)
O
NAC
SG
OH
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 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;303:1026-1029
Other Benefits of NAC
• Improved oxygen delivery and utilization in
extrahepatic organs
• Helps preserve cerebral blood flow
• Possibly due to mediation of microvascular
tone
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
What about IV NAC?
Con
Pro
• 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
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
Non-acute ingestions
• Hepatotoxicity is rare
• Usually seen in pediatric population
– Poor label-reading
– Mom & Dad…
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
Salicylates
OH
C O
O
O C CH3
Acetyl salicylic acid
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
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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
Pharmacokinetics
• pKa of 3.5
• Peak serum levels in 30 minutes
• Absorbed well in stomach and intestine
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*
Toxicity
•
•
•
•
•
•
•
•
Primary respiratory stimulant
Tinnitus
Gastrointestinal upset and pylorospasm
Diaphoresis
Mental status changes
Acute Lung Injury
Increased brain utilization of glucose
Metabolic acidosis
Metabolism
CH3
OH
O
C O
Acetyl
Salicylic
acid
O
Methyl
salicylate
C O
O C CH3
OH
OH
C O
OH
2.5%
pH
Urine
H N CH 2COOH
C O
OH
Absorbed, Protein
binding
Salicylic acid
OH
O C6H9O6
OH
C O
C O
C O
O C6H9O6
OH
OH
HO
Salicyluric acid
Ether glucuronide
Ester glucuronide
Gentisic acid
Overdose!
CH3
OH
O
C O
Acetyl
Salicylic
acid
O
Methyl
salicylate
C O
O C CH3
OH
OH
C O
OH
2.5%
pH
Urine
Salicylic acid
SATURATED
H N CH 2COOH
C O
OH
More ASA Absorbed
Decreased Protein
binding
OH
O C6H9O6
OH
C O
C O
C O
O C6H9O6
OH
OH
HO
Salicyluric acid
Ether glucuronide
Ester glucuronide
Gentisic acid
Normal Energy Generation
Glycolysis
Glucose
Pyruvate
Pyruvate
decarboxylase
Kreb’s
Cycle
CO2
Oxidative Phosphorelation
NADH2
H2O
ATP
Salicylate Uncoupling
ATP
Glycolysis
Glucose
Pyruvate
Pyruvate
decarboxylase
Kreb’s
Cycle
CO2
Lactate
Oxidative Phosphorelation
NADH2
H2O
SALICYLATES
ATP
MUDPILES
•
•
•
•
•
Methanol
Uremia
DKA, SKA, AKA
Paraldehyde
INH, Iron, Infection
• Lactate
• Ethylene glycol
• Salicylates
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
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
Rapid ASA Confirmation
OH
OH
C O
C O
OH
+ FeCl2
Salicylic Acid
Fe
OH
(Purple colored complex)
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?
GI Decontamination
• Activated Charcoal
• Multiple Dose Activated Charcoal (MDAC)
• Whole Bowel Irrigation (enteric coated)
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
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
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;41:475-484
Effects of Urinary Alkalinization
Prior to Alkalinization
Tissues pH 6.8
Plasma pH 7.1
Urine pH 6.5
HA
HA
HA
H+ + A-
H+ + A-
H+ + A-
Temple AR. Acute and chronic effects of aspirin toxicity and their treatment. Arch Intern Med 1981;141:367
Effects of Urinary Alkalinization
After Alkalinization
Tissues pH 6.8
Plasma pH 7.4
Urine pH 8
HA
HA
HA
H+ + A-
H+ + A-
H+ + A-
Temple AR. Acute and chronic effects of aspirin toxicity and their treatment. Arch Intern Med 1981;141:367
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
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