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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
[email protected]
Karen, PharmD
Sara, PharmD, CSPI
Rose, PharmD, CSPI
Robert, PharmD, CSPI
Stevie, PharmD, CSPI
Holly, PharmD, CSPI
Ina Bawaya,
Educator
Drug Info.
Jess Benson,
Steven Seifert, MD
PharmD, DABAT,
Medical Director
Managing Director
Lee, PharmD, CSPI
Jennifer, PharmD, CSPI LaDonna PharmD, CSPI
Damon, PharmD, CSPI
Gordon, PharmD, CSPI
Lauri Ivy, Admin
Asst.
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
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
http://www.fda.gov/AdvisoryCommittees/Calendar/ucm143083.htm
APAP Liquid Preparations
• Elixir: 160mg/5mL
• Drops: 80mg/0.8mL = 500
mg/5mL
APAP Metabolism
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
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
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
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
Level-Based Risk
• Caveats
• Only for acute ingestion
• Not useful < 4 h
• Less useful > 12 h
• Cannot be used for
chronic ingestion or subacute over > 8 h
• May need multiple levels
for delayed-release;
large amts or if
combined with opioids or
anticholinergics
Caution
• No clear cutoff for toxicity
– 1.6% to 10% (abstinent alcoholics)
risk of hepatotoxicity below 150
mcg/mL @ 4 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. 2008 May;42(3):213-8. Epub 2008 Mar 20
2Doyon S, Klein-Schwartz W. Acad Emerg Med. 2009 Jan;16(1):34-9
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
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
Course of Liver Injury w/o NAC
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 AST/ALT @ end of NAC
• Acute ingestion with hepatotoxicity
– PO or IV NAC with continuation until
clearly improving, transplant or death
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
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;335:1572-1573.
2Keays R, Harrison PM, Wendon JA, et al. BMJ 1991;303:1026-1029.
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
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
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
Questions?