1. Acetaminophen TIP Session IV

2. 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)

3. 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 p- aminophenol itself is too toxic for therapeutic purposes.  Acetaminophen is weakly acidic (pK a = 9.51) and synthesized by the acetylation of p-aminophenol

4. 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

5. METABOLISM OF ACETAMINOPHEN  Acetanilide and phenacetin are metabolized to acetaminophen.  Undergoes rapid first- pass 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.

6. Metabolism of Acetaminophen continued A minor, but significant, product of both acetaminophen and phenacetin is the N- hydroxyamide 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.

7. 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

8. 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.

9. 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.

10. Acetaminophen Analgesic Low effect on peripheral COX Few drug-drug interactions Not anti- inflammatory Liver toxicity

11. 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