Acetaminophen

and
Salicylates

Toxicity and Management

Joseph Rella, MD
Emergency Medicine
NJMS
Substances most frequently involved
in Human exposures
• Analgesics 284,906
• Cosmetics and personal care products 214,780
• Cleaning Substances 214,091
• Sedative-Hypnotics-Antipsychotics 141,150
• Foreign bodies 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 382
• Opioids 307
• Cardiovascular drugs 252
• Antidepressants 210
• Stimulants and street drugs 203
• Acetaminophen (alone or combo) 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 CH 3

OH
 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
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
 O
Metabolism O
H C UDP-glucuronosyl- H C
N CH3 transferase N CH3
Urine <5% 50%

40
Ph %
Acetaminophen en -
os O C6H8O6
u lfo
tra Acetaminophen glucuronide
n sfe
OH r as
e O

H C
CytoP450 N CH3
5-15%

O
O
C
C N CH 3 O SO3
-
N CH3
Acetaminophen sulfate

Glutathione (GSH) SG
OH
O
N-acetylparabenzoquinoneimine Acetaminophen glutathione conjugate
 O
Overdose!
O
H C UDP-glucuronosyl- C
d
H
CH3 CH3
Urine
N transferase

at e N

<5%

t ur
Acetaminophen
Sa
Ph
en
osu
lfo
O C6H8O6
-

tra
n sf e
ras
OH e
O
O
H C
39% C CH3
CytoP450 N CH3 N

SH)
G
e( SG
O
h ion OH
t
C luta Acetaminophen glutathione conjugate O SO3
-
N CH3 G
Acetaminophen sulfate

NAPQI Binding to cellular proteins

leading to hepatic and renal
O
N-acetylparabenzoquinoneimine 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
 Most people took less than they
say they did, except for those
who took more.
Number of people

amount
 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
150 for Toxicity
100
APAP concentration mcg/mL

50 Toxicity
Unlikely
10

4 8 12
Time after ingestion
16 20 24
 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;319:1557-1562
• 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 O
H C UDP-glucuronosyl- H C
N CH3 transferase N CH3
Urine <5% 50%

40%
Acetaminophen Ph -
en O C6H8O6
os
ulf
ot r
an Acetaminophen glucuronide
sfe
OH r as
NAC e O

H C
CytoP450 N CH3
5-15%

O
O
C
NAC N
C
CH3 NAC N CH3 O SO3
-

Acetaminophen sulfate

Glutathione (GSH) SG
OH
O NAC
 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?
Pro Con
• No vomiting • Anaphylactoid response
• Consistent delivery • No first-pass effect
• Only route studied for • More costly
fulminant hepatic • No guarantee of sterility
failure or pyrogen free
• Pregnancy?
 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
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
 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 Methyl
Acetyl C O O C O salicylate
Salicylic O C CH3 OH
acid
OH
C O
OH
2.5% Absorbed, Protein
Urine
pH Salicylic acid binding

H N CH 2COOH OH O C6H 9O6 OH

C O C O C O C O
OH O C6H9O6 OH OH

HO

Salicyluric acid Ether glucuronide Ester glucuronide Gentisic acid

 Overdose!
CH3
OH O Methyl
Acetyl C O O C O salicylate
Salicylic O C CH3 OH
acid
OH
C O
OH
2.5% More ASA Absorbed
Urine
pH Salicylic acid Decreased Protein
binding
SATURATED
H N CH 2COOH OH O C6H 9O6 OH
C O C O C O C O
OH 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
H2O NADH2

ATP
 Salicylate Uncoupling
ATP

Glycolysis
Glucose Pyruvate Pyruvate
decarboxylase
Kreb’s
Cycle CO2

Lactate
Oxidative Phosphorelation
H2O NADH2
SALICYLATES

ATP
 MUDPILES
• Methanol • Lactate
• Uremia • Ethylene glycol
• DKA, SKA, AKA • Salicylates
• Paraldehyde
• INH, Iron, Infection
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
Fe
OH
OH
+ FeCl2
Salicylic Acid (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