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?
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
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