Acetaminophen and

Salicylates

Toxicity and Management

Joseph Rella, MDEmergency Medicine

NJMS

Substances most frequently involved in Human exposures

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

284,906214,780214,091141,150120,752

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)

382307252210203352

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)

OH

NH C

O

CH3

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

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Metabolism

N-acetylparabenzoquinoneimine Acetaminophen glutathione conjugate

Acetaminophen glucuronide

Urine

OH

NH C

O

CH3

NH C

O

CH3

O SO3-

NCO

CH3

O

NCO

CH3

OHSG

Acetaminophen

Acetaminophen sulfate

Phenosulfotransferase

NH C

O

CH3

O C6H8O6-

UDP-glucuronosyl-transferase

50%

40%

<5%

5-15%CytoP450

Glutathione (GSH)

Overdose!

N-acetylparabenzoquinoneimine

OH

NH C

O

CH3

NH C

O

CH3

O SO3-

NCO

CH3

O

NCO

CH3

OHSG

Acetaminophen

Acetaminophen sulfate

Phenosulfotransferase

NH C

O

CH3

O C6H8O6-

UDP-glucuronosyl-transferase

<5%

Acetaminophen glutathione conjugate

CytoP450

Glutathione (G

SH)

Urine

Satura

ted

Binding to cellular proteinsleading to hepatic and renal

injury

39%

NAPQI

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.

amount

Num

ber o

f peo

ple

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 Nomogram500

200150

100

50

10

4 8 12 16 20 24

APA

P co

ncen

tratio

n m

cg/m

L

Potential for Toxicity

ToxicityUnlikely

Time after ingestion

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%

• Factor V < 50% of normal• Age• Absence of HBsAg• Α fetoprotein level

PPV=90% NPV=94%

Laboratory predictors of poor prognosis:

The Clichy Criteria

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

Acetaminophen glucuronide

Urine

OH

NH C

O

CH3

NH C

O

CH3

O SO3-

NCO

CH3

O

NCO

CH3

OHSG

Acetaminophen

Acetaminophen sulfate

Phenosulfotransferase

NH C

O

CH3

O C6H8O6-

UDP-glucuronosyl-transferase

50%

40%

<5%

5-15%CytoP450

Glutathione (GSH)

NAC

NAC

NAC

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?

• 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

Pro Con

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

COH

OO C

OCH3

Acetyl salicylic acid

Got Salicylates?

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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

C OOH

OH

HO

C OO

OH

C6H9O6C OOH

O C6H9O6CNH CH2COOH

OOH

COH

OOH

COCH3

OOH

COH

OO C

OCH3

Salicyluric acid Ether glucuronide Ester glucuronide Gentisic acid

AcetylSalicylicacid

Methylsalicylate

2.5%pHUrine Absorbed, Protein

bindingSalicylic acid

Overdose!

C OOH

OH

HO

C OO

OH

C6H9O6C OOH

O C6H9O6CNH CH2COOH

OOH

COH

OOH

COCH3

OOH

COH

OO C

OCH3

Salicyluric acid Ether glucuronide Ester glucuronide Gentisic acid

AcetylSalicylicacid

Methylsalicylate

2.5%pHUrine More ASA Absorbed

Decreased Proteinbinding

Salicylic acid

SATURATED

Normal Energy Generation

Glucose Pyruvate Kreb’s Cycle CO2

NADH2H2O

ATP

Glycolysis Pyruvate decarboxylase

Oxidative Phosphorelation

Salicylate Uncoupling

Glucose Pyruvate Kreb’s Cycle CO2

NADH2H2O

ATP

SALICYLATES

ATP

Lactate

Glycolysis Pyruvate decarboxylase

Oxidative Phosphorelation

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

COH

O

OH

FeCOH

OOH

+ 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

Tissues pH 6.8 Plasma pH 7.1 Urine pH 6.5

HA

H+ + A-

HA

H+ + A-

HA

H+ + A-

Prior to Alkalinization

Temple AR. Acute and chronic effects of aspirin toxicity and their treatment. Arch Intern Med 1981;141:367

Effects of Urinary Alkalinization

Tissues pH 6.8 Plasma pH 7.4 Urine pH 8

HA

H+ + A-

HA

H+ + A-

HA

H+ + A-

After Alkalinization

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