1. ACETAMINOPHEN Steven A. Seifert, MD, FACMT, FAACT
Professor, Medical Toxicology
University of New Mexico School of Medicine
Medical Director
New Mexico Poison & Drug Information Center 1

2. Jess Benson, PharmD, DABAT, Managing Director
Sara, PharmD, CSPI
Karen, PharmD
Rose, PharmD, CSPI
Robert, PharmD, CSPI
Holly, PharmD, CSPI
Stevie, PharmD, CSPI
Ina Bawaya, Educator
Drug Info.
Jess Benson, PharmD, DABAT,
Managing Director
Steven Seifert, MD
Medical Director
Lee, PharmD, CSPI
Lauri Ivy, Admin Asst.
Jennifer, PharmD, CSPI
LaDonna PharmD, CSPI
Damon, PharmD, CSPI
Gordon, PharmD, CSPI

3. Common Things Are Common
Analgesics (2008 NPDS)
Exposures
13.3% of all human exposures (#1)
17.2% of adult exp. (#1)
9.7% of pediatric (<6y) exp. (#2)
Deaths
Analgesics #1 in fatalities
APAP in combination #5
APAP alone #8
ASA alone #13

4. FDA Advisory Committee – June 30, 2009
Lowering the MDD of nonprescription APAP for adults, MDD not specified (21 – 6)
Reduce the maximum single adult dose and tablet strength to 650 mg (24 – 13)
1,000-mg dose be prescription-only (26 – 11)
Eliminating prescription acetaminophen combination products (20 -17)
If APAP-combination prescription drugs stay on the market, they carry a black-box warning (36 – 1)
As of 10/25/10, none of the recommendations have been acted upon

6. APAP Liquid Preparations
Elixir: 160mg/5mL
Drops: 80mg/0.8mL = 500 mg/5mL

7. APAP Metabolism 2

8. 4

9. APAP Metabolism
Primary process is sulfation: high affinity, low capacity
Secondary is glucuronidation: lower affinity, high capacity
P450 pathway (CYP2E1, 1A2, & 3A4) when 1o and 2o saturated.
Generates N-acetyl parabenzoquinone imine (NAPQI) and a semiquinone=reactive species
Ultimately, APAP-mercapturate formed by neutralization of NAPQI w/ glutathione 3

10. Risk Factors for Liver Injury
Rate of production of NAPQI
Amount and production rate of native glutathione
Regenerative ability of liver
These are all dependent on:
Quantity & rate of APAP absorption
Metabolic activity of CYP2E1, 1A2, & 3A4, rate of elimination/disposition of APAP metabolites, genetics
Nutritional status
Only quantifiable factors are total amount taken and peak levels

11. Triage and Treatment In acute OD
We use total dose for triage decisions
We use blood level (> 4 h) for treatment
In chronic OD or unknown
We use history and/or lab and/or empirical tx

12. Dose-based Risk Referral protocols
Poor correlation between history and dose
Pediatric, Acute: > 200 mg/kg
Adult, Acute: > 150 mg/kg
Chronic (<24 hours):
More than 10 gms in 24 hrs in adults
More than 200 mg/kg in 24 hrs in peds
Repeated Supratherapeutic Ingestion (RSI)
Definition: More than maximum rec’d dose for more than 24 hours (4 g/d)
Referred in for lab evaluation

13. Level-Based Risk Caveats Only for acute ingestion Not useful < 4 h
Less useful > 12 h
Cannot be used for chronic ingestion or sub- acute over > 8 h
May need multiple levels for delayed-release; large amts or if combined with opioids or anticholinergics

14. Caution No clear cutoff for toxicity
1.6% to 10% (abstinent alcoholics) risk of hepatotoxicity below hr1
Patients tx w/in 8 hrs w/ IV NAC developed hepatotoxicity in 5.2% of cases2
Hepatotoxicity = AST or ALT > 1,000
1Ali FM, Boyer EW, Bird SB. Alcohol May;42(3): Epub 2008 Mar 20
2Doyon S, Klein-Schwartz W. Acad Emerg Med Jan;16(1):34-9 17

15. Glutathione Glutathione is a tripeptide
Glutamate-Cysteine-Glycine
Need to provide adequate supply of intracellular glutathione in locations of p450 enzymes (liver, kidney)
Other beneficial effects may make it useful in late presenters and hepatic failure from other causes
But does not cross cell membranes

16. N-Acetylcysteine (NAC)
N-actylecysteine (NAC) crosses cell membrane, is de-acetylated, and thus provides intracellular cysteine
Rate-limiting step in the production of intracellular glutathione
If NAC started before depletion of glutathione (~8 h), highly unlikely to see significant hepatotoxity

17. Course of Liver Injury w/o NAC7

18. Prevention of Injury Acute Exposure
Time to first NAC dose < 8 hours
Treat if above 150 mcg/mL line
PO / IV protocols w/ equal efficacy
Must have no APAP at end of IV NAC
Acute & > 8 hrs to first NAC dose
IV or PO NAC x 36 hrs from ingestion
Can stop IF non-detectable APAP and no increase in end of NAC
Acute ingestion with hepatotoxicity
PO or IV NAC with continuation until clearly improving, transplant or death

19. Prevention of Injury RSI
Often detected serendipitously in ED
Management
IF no measurable APAP (<10 mcg/mL) AND no increased AST/ALT
No treatment
IF measurable APAP
Admit for 24 hrs NAC, recheck APAP/AST/ALT and discontinue if all negative
IF elevated AST/ALT
Treat as for acute presentation with hepatotoxicity

20. Very Late Presenters
Increased survival in patients presenting in fulminant hepatic failure tx w/ IV NAC.1,
Retrospective (n=100): Mortality was 37% in patients who received NAC compared with 58% in patients not given NAC1
Prospective (n=50): Survival was significantly higher with NAC (48%) than controls (20%)2
NAC treated patients
Had a lower incidence of cerebral edema (40% v. 68%)
Developed less hypotension requiring inotropic support (48% v. 80%)
Liver function was unchanged
1Harrison PM, Keays R, Bray GP, et al. Lancet 1990;335:
2Keays R, Harrison PM, Wendon JA, et al. BMJ 1991;303: 37

21. Transplant Referral and Outcome Prognostic Factors
Possible need for transplant (alert team)
Arterial pH < 7.3 after fluid replacement
INR > 6.5
Serum Cr > 3.4
Encephalopathy, grade 3 or 4
Grade 3: Somnolence, confusion, gross disorientation
Grade 4: Coma
During hospital course
Poor
Development of King’s criteria
Persistent elevation of lactate > 12
Good
Phosphorus < 3.0
Spontaneously improving INR, ammonia, and mental status

22. What is the Optimal NAC Route?
No class “A” studies and no controlled study has compared IV to PO
PO v. IV efficacy appears equivalent in early presenters
Adverse events
PO: Nausea/vomiting; usually first 1 – 2 doses
IV: Allergic rxns
Minor rxns ~ 14%
Severe ~ 0.1% to 0.3%
Current poison center recs: Use PO unless specific indications for IV or CI to PO
IV indications: Late presentation, >8 h, acidosis, encephalopathy, renal injury, pregnancy, persistent vomiting
PO contraindications: CNS depression, caustics, hydrocarbons, obstruction 19

23. Proposed UNMH Actions Acetaminophen Task Force approved the following:
Pharmacy should stock only combination agents with acetaminophen 325mg
Pharmacy should only stock acetaminophen 325mg and maximum single adult dose should be 650mg
Combination agents should be avoided in the inpatient, oxycodone and acetaminophen should be administered as separate agents.
The newly implemented total daily acetaminophen dose calculator should be programmed to fire at 3,200mg.
Over-the-counter combination agents containing acetaminophen should be removed from the formulary
Stock only elixir (160 mg/5 mL) concentration
Plan to obtain input from providers prior to implementation

24. Questions?