Mechanisms of Action of Acetaminophen
Condition: Myocardial Infarction; Arthritis
MeSH terms: Myocardial Infarction; Infarction
Study type: Interventional

Summary: 
      This research study investigates whether the ability of aspirin to reduce the risk of heart
      attacks may be diminished by the administration of acetaminophen. Patients who have heart
      disease are often prescribed aspirin because of its unique ability to permanently prevent
      platelets from aggregating and forming a blood clot. Such blood clots cause heart attacks
      when they form in a blood vessel that supplies the heart with oxygen rich blood. Some of
      these same patients also take acetaminophen everyday for relief from arthritis pain. Higher
      doses of acetaminophen may also have the ability to prevent the platelets from clotting,
      however only temporarily. Therefore, this study evaluates whether the timing of the
      administration of acetaminophen (before or after aspirin) interferes with the permanent blood
      clotting effects of aspirin.

      The primary hypothesis is that acetaminophen given two hours before aspirin will antagonize
      the effects of aspirin, while reversing the order of administration will not.
    

Detailed description: 
      Acetaminophen has antipyretic and moderate analgesic properties, but largely lacks
      anti-inflammatory activity. While its mechanism of action is not entirely understood, it is
      probably both an isoform nonspecific and partial cyclooxygenase (COX) inhibitor in humans at
      doses commonly taken for mild pain and pyrexia, such as 1000 mg. Although no inhibition of
      platelet aggregation is observed at this dosage, platelet thromboxane formation by COX is
      depressed by roughly 40%. Epidemiological studies suggest that at higher doses, 2000 mg and
      above, acetaminophen exhibits a gastrointestinal adverse effect profile indistinguishable
      from traditional, nonspecific NSAIDs. Thus, it is possible that maximal COX inhibition is
      achieved at higher doses. Interestingly, complete COX inhibition by non-selective COX
      inhibitors has the potential to antagonize the irreversible platelet inhibition induced by
      aspirin. In contrast to reversible inhibitors, aspirin acts by acetylation of a serine
      residue in the substrate binding channel of COX. For example, ibuprofen, a reversible and
      non-selective COX inhibitor, is thought to prevent aspirin from gaining access to this target
      site. This study investigates, whether COX inhibition by acetaminophen is dose dependent in
      humans and whether acetaminophen interacts with the irreversible COX inhibition by low dose
      aspirin. It addresses the dose-related effect of acetaminophen on COX activity and assesses
      potential pharmacological interactions with low dose aspirin in normal healthy volunteers.
      The primary hypothesis is that administrating acetaminophen before aspirin would antagonize
      the irreversible effects of aspirin, as assessed by the measurement of serum thromboxane B2
      24 hrs after the administration of the first study drug on day 6 of combination therapy.

      The second aim will determine the effects of acetaminophen on oxidant stress and
      cyclooxygenase activity in patients who smoke. While the structural interaction of
      acetaminophen with COX is unknown, it may inactivate the enzyme by a molecular mechanism
      different from other NSAIDs. Thus, acetaminophen, which is a good reducing agent, might act
      to reduce COX from its active, oxidized form. When uninhibited, the peroxidase component of
      this bifunctional enzyme oxidizes its catalytic center to generate a tyrosyl radical that is
      required for its activity. Indeed, some reducing agents have the capacity to prevent COX
      activation in vitro. If reduction were the basis for COX inhibition by acetaminophen in vivo,
      it would be expected to be less pronounced under conditions of high peroxide tone, as occurs
      in inflammation. Indeed, acetaminophen, which is a phenol derivative, may act as a free
      radical scavenging antioxidant like other phenolic compounds, such as vitamin E and has been
      shown to alleviate oxidative damage in model systems. This study explores the potential
      antioxidant effect of acetaminophen in smokers. Such individuals represent a human model of
      oxidant stress. Novel approaches to the quantitative assessment of free radical induced
      damage to lipids are applied, which are elevated in smokers. Additionally, it is determined
      whether COX inhibition by acetaminophen is conditioned by oxidant tone in vivo.

      The third aim, will compare the degree of COX inhibition by acetaminophen with that of a
      thoroughly characterized nonselective COX inhibitor, ibuprofen.
    

Intervention name(s): Aspirin First; Aspirin Last; Acetaminophen 1000 mg/d; Acetaminophen 4000 mg/d; Ibuprofen 800 mg/d
Intervention type(s): Drug; Drug; Drug; Drug; Drug
Intervention description(s): Crossover period Aspirin First: Subjects will receive 81 mg aspirin at approximately 8 am followed by acetaminophen at approximately 10 am.; Crossover period Aspirin Last: Subjects will receive acetaminophen at approximately 8 am followed by 81 mg aspirin at approximately 10 am.; Subjects will receive a daily oral dose of 1000 mg acetaminophen for six days each administered at 8 AM.; Crossover period Acetaminophen 4000 mg/d: Acetaminophen (1000 mg p.o.) orally at 8 AM, 2 PM, 8 PM and 2 AM for 3 days. The last dose will be administered on day four at 8 AM.; Crossover period Ibuprofen 800 mg/d: Ibuprofen (200 mg) orally at at 8 AM, 2 PM, 8 PM and 2 AM for 3 days. The last dose will be administered on day four at 8 AM.
Intervention MeSH terms: Aspirin; Acetaminophen; Ibuprofen
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: acetaminophen; low dose aspirin; cyclooxygenase; prostaglandin; drug interaction; platelet inhibition; urinary prostaglandin metabolites; oxidant stress; smoking