Acetaminophen: Difference between revisions

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| mechanism = <vote slug="apap-mech-claim">Acetaminophen's analgesic and antipyretic actions are incompletely characterized; central COX inhibition (particularly the COX-2 splice variant sometimes called COX-3, and inhibition of arachidonic acid pathways in CNS at low peroxide concentrations) is the leading hypothesis, with possible contribution from descending serotonergic pathways and TRPV1 modulation by the AM404 metabolite.</vote> The absence of meaningful peripheral cyclooxygenase inhibition explains the lack of antiplatelet and anti-inflammatory effect compared with NSAIDs, and the gastroprotective profile. '''Dose-dependent hepatotoxicity''' via the CYP2E1 metabolite N-acetyl-p-benzoquinone imine (NAPQI) once glutathione is depleted; N-acetylcysteine is the antidote and is most effective within 8-10 hours of overdose<ref name="tylenol-label" />.

}}

== Overdose and toxicity ==

For a single acute ingestion at a known time, the Rumack-Matthew nomogram guides

whether to treat: a serum acetaminophen concentration is drawn no earlier than 4 hours

after ingestion and plotted against time.<ref>Rumack BH, Matthew H. Acetaminophen

poisoning and toxicity. Pediatrics. 1975;55(6):871-876.</ref> In the United States the

treatment line begins at 150 micrograms/mL at 4 hours (set 25% below Rumack and Matthew's

original 200 micrograms/mL line, the FDA-adopted treatment threshold); a level on or above the line

indicates N-acetylcysteine, a level below it does not.<ref>Wallace CI, Dargan PI, Jones

AL. Paracetamol overdose: an evidence based flowchart to guide management. Emerg Med J.

2002;19(3):202-205.</ref> The nomogram does NOT apply to chronic or repeated

(staggered) ingestion, an unknown ingestion time, levels drawn before 4 hours, or

modified/extended-release products; in those situations N-acetylcysteine is given

empirically with serial transaminase and acetaminophen monitoring.

Two established N-acetylcysteine regimens are used. The intravenous 21-hour (Prescott)

regimen gives 150 mg/kg as a loading dose, then 50 mg/kg over the next 4 hours, then

100 mg/kg over the following 16 hours.<ref>Prescott LF, Illingworth RN, Critchley JA, et

al. Intravenous N-acetylcysteine: the treatment of choice for paracetamol poisoning. Br

Med J. 1979;2(6198):1097-1100.</ref> The oral 72-hour regimen gives a 140 mg/kg loading

dose, then 70 mg/kg every 4 hours for 17 doses.<ref>Smilkstein MJ, Knapp GL, Kulig KW,

Rumack BH. Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose.

N Engl J Med. 1988;319(24):1557-1562.</ref> Treatment is most effective when started

within 8 hours of ingestion, but is still given later, and in established liver injury or

acute liver failure, where it improves outcomes. Massive or late-presenting overdose may

require extended or increased dosing. This is reference information, not a treatment

protocol; overdose is a medical emergency managed by clinicians and poison control.

== Combination products and the 325 mg limit ==

Because acetaminophen is present in many products at once -- prescription opioid

combinations (e.g. hydrocodone/acetaminophen, oxycodone/acetaminophen) and over-the-

counter cold, flu, and sleep products -- people can exceed the maximum daily dose without

realizing it by stacking several acetaminophen-containing products, a leading route to

unintentional hepatotoxicity. In January 2011 the FDA acted on this risk for PRESCRIPTION

acetaminophen products: it asked manufacturers to limit acetaminophen to 325 mg per dosage

unit in prescription combination products (a change manufacturers completed by 2014), and it

required a boxed warning on all prescription products containing acetaminophen highlighting

the potential for severe liver injury.<ref>U.S. Food and Drug Administration. Drug Safety

Communication: Prescription acetaminophen products to be limited to 325 mg per dosage unit;

boxed warning will highlight potential for severe liver failure. January 13, 2011.</ref>

Over-the-counter acetaminophen products instead carry a Drug Facts "Liver warning," not a

boxed warning. Checking every product label for acetaminophen (sometimes abbreviated APAP)

and summing the total is the practical safeguard.

== References ==

MDElliottMD (talk | contribs)