Acetaminophen
TIP Session IV
History
Acetaminophen (paracetamol) was
introduced in 1893 but remained
unpopular for more than 50 years, until it
was observed that it is a metabolite of
both acetanilide and phenacetin.
 It remains the only useful agent of this
group and is widely used as a
nonprescription antipyretic/analgetic
under a variety of trade names (Tylenol,
Patrol, and Tempera)

Structure of Acetaminophen
p-aminophenol derivatives
Based on the comparative toxicity of acetanilide
and acetaminophen, aminophenols are less toxic than
the corresponding aniline derivatives, although paminophenol itself is too toxic for therapeutic
purposes.
Acetaminophen is weakly acidic (pKa = 9.51) and
synthesized by the acetylation of p-aminophenol
Acetaminophen
It is weakly bound to plasma proteins (18–25%)
It is an antipyretic/analgetic that is recommended for
those individuals displaying an allergy or sensitivity to
aspirin.
 It does not possess anti-inflammatory activity, but it
will produce analgesia in a wide variety of arthritic
and musculoskeletal disorders
 The usual adult dose is 325 to 650 mg every 4 to 6
hours. Doses of greater than 2.6 g/day are not
recommended for long-term therapy because of
potential hepatotoxicity issues.
 Unlike aspirin, it is stable in aqueous solution, making
liquid formulations readily available, a particular
advantage in pediatric cases


METABOLISM OF
ACETAMINOPHEN
Acetanilide
and
phenacetin are
metabolized to
acetaminophen.
Undergoes rapid firstpass metabolism in the GI
tract primarily by
conjugation reactions, with
the O-sulfate conjugate
being the primary
metabolite in children and
the O-glucuronide being
the primary metabolite in
adults.
Metabolism of Acetaminophen
continued
A minor, but significant, product of both
acetaminophen and phenacetin is the Nhydroxyamide produced by a CYP2E1 and CYP3A4.
 The CYP2E1 is the rate-limiting enzyme that initiates
the cascade of events leading to acetaminophen
hepatotoxicity; in the absence of this cytochrome
P450 enzyme, toxicity will only be apparent at high
concentrations.
 The N-hydroxyamide is then converted to a reactive
toxic metabolite, an acetimidoquinone, which has
been suggested to produce the nephrotoxicity and
hepatotoxicity associated with acetaminophen and
phenacetin.

Mechanism of Action

Despite the extensive use of acetaminophen, the mechanism of
action is not fully understood.

May inhibit pain impulses by exerting a depressant effect on
peripheral receptors

The fact that acetaminophen is an effective antipyretic/analgetic but
an ineffective anti-inflammatory agent may result from its greater
inhibition of prostaglandin biosynthesis via inhibition of the COX-3
isoform in the CNS compared with that in the periphery.

Other authors claim that the mechanism of action of
acetaminophen is thought to involve inhibition of COX-2, and this
fits with the therapeutic profile of the recently discovered,
powerful, and selective COX-2 inhibitors
Side Effects
In recommended therapeutic doses,
acetaminophen does not cause gastric
irritation, gastric erosions, occult or overt
gastrointestinal blood loss, or ulcers.
 Overdoses of acetaminophen can
produce potentially fatal hepatic necrosis,
renal tubular necrosis, and hypoglycemic
coma.

Drug Interactions
Hepatic necrosis develops at much lower doses
of acetaminophen in some heavy drinkers than
would be expected.
 At 4 g per day, acetaminophen has been reported
to potentiate the response to oral anticoagulants,
increasing prothrombin time (INR values) two to
three times.
 May also interfere with the enzymes involved in
vitamin K-dependent coagulation factor synthesis
 Acetaminophen forms “sticky” mixtures with
diphenhydramine HCl and discolors under humid
conditions in the presence of caffeine or codeine
phosphate.

Acetaminophen

Analgesic

Not antiinflammatory

Low effect on
peripheral COX

Liver toxicity

Few drug-drug
interactions
References
Much of the information provided here
was adapted from:
 Lemke, T. L., Williams, D. A., Roche, V. F., &
Zito, S. W. (2008). Foye's Principles of
Medicinal Chemistry . Philadelphia: Wolters
Kluwer.
 Rx List Inc. (2009). Acetaminophen.
Retrieved February 14, 2009, from RxList:
http://www.rxlist.com/tylenol-drug.htm
