Acetaminophen

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Contents 1 Introduction 2 Indications 3 Contraindications 4 Dosage 5 Dosage-adjustment-in-renal-failure 6 Pharmacokinetics 7 Adverse-effects 8 Drug-interactions 9 Laboratory 10 Mechanism-of-action 11 Notes 12 More General Terms 13 Additional Terms 14 Internet Database 15 References

Introduction

• Tradenames: Tylenol, Paracematol, Panadol, Tempra, Datril.

Indications

• treatment of pain & fever
• minimal anti-inflammatory effects

Contraindications

• Caution: in patients with G6PD deficiency
  
• pregnancy category = a
• safety in lactation = +

Dosage

• 650 mg PO/ PR every 4 hours
• 500 mg PO/ PR every 4 hours
• max = 3000 mg/day [13] (less for chronic alcohol users)

• Pediatrics: 15 mg/kg/dose (max 80 mg/kg/day)
• Tabs: 160, 325, 500 mg.
• Tabs: 500 mg tablets may be withdrawn from US market [12]
• Tabs: (chewable): 80 mg.
• Suppositories: 120, 325, 650 mg.
• Elixir: 160 mg/5 mL.
• Drops: 80 mg/0.8 mL dropperful.

Dosage-adjustment-in-renal-failure

*  creatinine            dosage 
*  clearance 
* 10-50 (mL/min)       every 6 hours 
* < 10  (mL/min)       every 8 hours (metabolites may accumulate)

Pharmacokinetics

• well absorbed orally
• metabolized in liver
• small amount metabolized to electrophilic aromatic intermediate
• metabolic capacity is saturatable
• 1/2 life (1-4 hours) shorter with pregnancy & hyperthyroidism, longer with liver disease
• onset of action is 15-30 minutes
• duration of action is 3-4 hours
• therapeutic-range: 10-30 ug/mL
• toxic-range: > 200 ug/mL 4 hours post ingestion
  

• elimination via liver
• elimination via kidney
• 1/2life = 1-4 hours
• protein binding = 20-50 %
• elimination by hemodialysis = +
• elimination by peritoneal dialysis = -

Adverse-effects

• rash
• nausea/vomiting
• blood dyscrasias
• nephrotoxicity with chronic use [5] (less than NSAIDs)
• hepatotoxicity
• hypertension, RR=1.34 with frequent use [6,8]
• asthma in children & adolescents [11]
  

• Overdose: (also see acetaminophen poisoning)

• antidote: N-acetylcysteine
• loading dose: 140 mg/kg PO
• 70 mg/kg PO every 4 hours for a total of 17 doses
• if 4 hour serum acetaminophen level is in the toxic range, all 17 doses of N-acetylcysteine must be given

Drug-interactions

• agents that increase acetaminophen hepatotoxicity

• carbamazepine, hydantoin, barbiturates, chronic alcohol use, rifampin

• actaminophen can elevate INR in patients takin warfarin
  
• drug interaction(s) of alcoholic beverage with acetaminophen
• drug interaction(s) of ethanol with acetaminophen

Laboratory

• specimen: serum, plasma ( EDTA, heparin)
• methods

• GLC, HPLC, GC-MS, EIA, FPIA

Mechanism-of-action

• direct action on hypothalamic temperature regulation centers
• inhibition of CNS prostaglandin synthetase
• minimal inhibition of cyclo-oxygenase

Notes

• FDA working group makes new recommendations for acetaminophen to reduce hepatic toxicity, May 2009 [9]. These include:

• using stronger warnings on the drug's label;
• limiting the single adult dose to a maximum of 650 mg;
• lowering the maximum daily dose for adults from 4000 mg to no greater than 3250 mg (less than that for chronic alcohol users);
• limiting tablet formulations for adults to 325 mg;
• restricting pediatric liquid formulations to a single mid-strength concentration;
• eliminating acetaminophen from combination products

More General Terms

• anilide
• analgesic (antalgic)
• antipyretic agent

Additional Terms

• acetaminophen in serum/plasma
• acetaminophen poisoning

Internet Database

PubChem: 1983

References

1. The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
2. Saunders Manual of Medical Practice, Rakel (ed), WB Saunders, Philadelphia, 1996, pg 1160-63
3. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
4. Prescriber's Letter 8(4):23 2001
5. Journal Watch 24(17):134, 2004 Curhan GC, Knight EL, Rosner B, Hankinson SE, Stampfer MJ. Lifetime nonnarcotic analgesic use and decline in renal function in women. Arch Intern Med. 2004 Jul 26;164(14):1519-24. PMID: [1]
6. Prescriber's Letter 12(9): 2005 Non-narcotic Analgesics and the Risk of Hypertension in Women Detail-Document#: [2] (subscription needed) [3]
7. Prescriber's Letter 13(7): 2006 Safe Use of Acetaminophen (Tylenol) Detail-Document#: [4] (subscription needed) [5]
8. Forman JP et al, Frequency of analgesic use and risk of hypertension among men. Arch Intern Med 2007, 167:394 PMID: [6]
9. Memorandum from Department of Health and Human Services, Food and Drugs Administration, Center For Drug Evaluation and Research dated May 22, 2009 regarding Report dated February 26, 2008 for meeting on June 29-30, 2009 Report is by: The Acetaminophen Hepatotoxicity Working Group Center for Drug Evaluation and Research Food and Drug Administration Department of Health and Human Services Recommendations for FDA Interventions to Decrease the Occurrence of Acetaminophen Hepatotoxicity [7]
10. Prescriber's Letter 16(7): 2009 New Warnings and Proposed Changes to Acetaminophen Products Detail-Document#: [8] (subscription needed) [9]
11. Beasley RW et al Acetaminophen Use and Risk of Asthma, Rhinoconjunctivitis and Eczema in Adolescents: ISAAC Phase Three. Am J Respir Crit Care Med. 2010 Aug 13. PMID: [10]
    - McBride JT. The association of acetaminophen and asthma prevalence and severity. Pediatrics 2011 Dec; 128:1181 PMID: [11]
12. FDA MedWatch, 01/13/11 Acetaminophen Prescription Products Limited to 325 mg Per Dosage Unit: Drug Safety Communication [12]
13. Johnson & Johnson McNeil Consumer Healthcare Announces Plans For New Dosing Instructions For Tylenol®Products [13]
14. Prescriber's Letter 18(9): 2011 COMMENTARY: Changes to Acetaminophen Labeling PATIENT HANDOUT: Safe Use of Acetaminophen (Tylenol) Detail-Document#: [14] (subscription needed) [15]

acetaminophen (Tylenol, Paracematol, Panadol, Tempra, Datril, APAP)