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Acetaminophen Toxicity
History
• Synthesized in 1877 in U.S.
• Extensive use began around 1947
• Initially prescription only in the U.S.
• Over the counter status gained in 1960
• Toxic effects first noted in U.S. in 1971
It’s everywhere!
• Acetaminophen is found in over 200 products
Actions
• Analgesia
Relieves mild to moderate pain
Efficacy equivalent to salicylates
Inhibits brain prostaglandin synthetase
Blocks pain impulses peripherally
• Antipyresis
• Efficacy similar to salicylates
• Inhibits prostaglandin synthetase in the
hypothalamus
Pharmacokinetics
• Absorption
– Rapidly absorbed from the GI tract
– Peak concentration usually occurs between 60 and
120 minutes
– Peak plasma levels almost always occur within 4
hours
Distribution
• V/d - 1.0 - 2.0 L/Kg
• Approximately 20% plasma protein bound
may increase to 50% in overdose
• Has been reported to cross the placenta
Metabolism
– Occurs via several pathways in the liver
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52% by sulfation
42% by glucuronidation
2% excreted unchanged in the urine
4% biotransformed by C-P450 MFO system into
an active intermediate NAPQI
NB: When large doses of APAP are ingested, both
the glucoronidation and sulfation pathways
become saturated, shunting more APAP toward
the P-450 system and increasing NAPQI
formation.
Metabolism
• When glutathione depletes to 30% of normal, NAPQI
accumulates.
• The NAPQI arylates to protein in the cytosol and
endoplasmic reticulum in the centrilobular zone of the
liver, producing cell necrosis and death.
• NAPQI is neutralized by glutathione
• NAPQI contains a sulfhydryl group. If all glutathione ...
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