Download Acetaminophen and Hepatotoxicity

PHYSICIANS EDUCATION GRAM
9/13/2011
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Acetaminophen and Hepatotoxicity – NEW MAX DOSE OF 3GM/DAY
Acetaminophen (APAP, paracetamol) is a widely used analgesic and antipyretic drug and is generally regarded as
safe at therapeutic doses. The past consensus on APAP dosing was that doses up to 4 grams per day could be
given without major problems. There is new evidence showing that hepatotoxicity can occur at doses less than 4
grams/day. Therefore, the maximum daily dose for acetaminophen (TylenolTM) has been changed to 3,000 mg
or 3 grams, and will be reflected on all dosing instructions and package inserts per the manufacturers.
Background:
• Acetaminophen toxicity is associated with hepatotoxicity
• New guidelines set the max daily dose of acetaminophen to 3g/day (changed from 4g/day)
• Hepatic necrosis after high doses is a well-known phenomenon
• There have been case reports of hepatotoxicity at doses <4g/day
Mechanism of Action:
• Acetaminophen is primarily metabolized by glucoronidation and sulphation
• A small fraction of acetaminophen is metabolized by the microsomal cytochrome P450 enzymes; The CYP 2E1 enzyme produces a
toxic metabolite of acetaminophen known as N-acetyl-p-benzo-quinone (NAPQI)
• At normal doses, only trace amounts of NAPQI are formed, which is bound to and inactivated by glutathione
• After excess doses or when CYP2E1 is induced (e.g. isoniazid) hepatic glutathione is depleted and can no longer
inactivate the increased amounts of NAPQI, which covalently binds to hepatocyte proteins and leads to cell death.
• In addition to enzyme-inducing drugs, other risk factors for paracetamol toxicity have been suggested such as alcoholism
and fasting or poor nutritional status.
Risk Factors/High Risk Patient Profile:
Patients at risk include the following risk factors/co-morbidities:
1. Patients who are fasting or have malnutrition
2. Patients with diabetes
3. Patients taking isoniazide or alcohol
4. Patients taking more the 3g Acetaminophen per day
Common Acetaminophen Products:
• Acetaminophen is commonly found in many over-the-counter products
and prescription products; note that the number of tablets per day that
can lead to toxicity is relatively low.
• Acetaminophen 325 mg: 9 tablets = close to 3 grams
• Acetaminophen 500mg: 6 tablets = 3 grams
• Vicodin ES: 4 tablets = 3 grams
COMMON ACETAMINOPHEN PRODUCTS
Prescription
OTC
Darvocet
Endocet
Tylenol
Vicodin
Tylenol# 3
Excedrin
Fioricet
Darvocet
Panadol
Norco
Lorcet
Nyquil
Percocet
Lortab
Theraflu
Fig. 1 Important metabolic pathways,
paracetamol conjugates, and factors
influencing toxicity. From: VITOLS: J
Intern Med, Volume 253(2). February
2003.95-98
CONCLUSION: Certain risk factors such as alcoholism, drug-interactions, poor nutritional status/fasting,
or genetics can predispose individuals to hepatotoxicity even at therapeutic doses.
Reference:
1.
Watkins, Paul B. Et al. Aminotransferase Elevations in Healthy Adults Receiving 4 Grams of Acetaminophen Daily A Randomized Controlled
Trial. JAMA 2006. 296 (1)
2.
Whitcomb,D.C. Association of Acetaminophen Hepatotoxicity with Fasting and Ethanol Use. JAMA 1994. 272:23
3.
Paracetamol Hepatotoxicity at Therapeutic Doses. Journal of Internal medicine 2003: 253
4.
Larson,AM.Et.al. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology.2005; 42 (6)
5.
Tylenol News. July 28, 2011. http://www.jnj.com
For comments or questions: Call Craig Stern, PharmD, Pharmacy Benefit
Consultant, at (888) 701-5438 or [email protected].
Pro Pharma Pharmaceutical Consultants, Inc. is not affiliated with any Health Plan, Pharmacy
Benefit Management (PBM) Company, or Pharmaceutical Manufacturer. This general
information is provided purely for your use and is not slanted toward any product or company.
P.O. BOX 280130 • NORTHRIDGE, CA 91328-0130 • (818) 701-5438 • FAX (818) 701-0249
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