MSK 01 and 04: Acetaminophen

Question 1

What is the mechanism of action of acetaminophen?

Answer 1

• suppresses PGE2 synthesis by weak inhibition of COX1 and COX2 in CNS, which reduces catalytic heme moiety to its resting state → lower catalytic activity (NSAIDs compete with arachidonic acid)

Question 2

What activity does acetaminophen NOT have?

Answer 2

• no anti-inflammatory activity – does not effectively suppress inflammation-related synthesis of prostaglandin E2 in tissues
• little effect on platelet function – does not effectively suppress synthesis of TXA2 in platelets

Question 3

What are 2 other proposed mechanisms of action of acetaminophen?

Answer 3

• may increase serotonin (5-HT) levels in CNS, leading to increased descending inhibition of pain
• in rodents: metabolite of acetaminophen (N-arachidonoylaminophenol (AM404)) increases anandamide (endocannabinoid) levels by inhibiting its reuptake – anandamide acts on cannabinoid 1 (CB1) receptor, which may contribute to analgesic and antipyretic actions

Question 4

What are the side effects of acetaminophen?

Answer 4

• no or little effect on GI tract, kidney function, blood pressure, or bleeding time
• 4 g/day: potential liver damage
• no advantage in exceeding 4g/day dosage

Question 5

Describe the metabolism of acetaminophen.

Answer 5

metabolized to toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI) formed by CYP2E1, which is then rapidly inactivated by glutathione sulfhydryl groups

• > 4g/day can lead to depletion of hepatic glutathione stores, and lead to potential liver damage (enhanced by alcohol)

Question 6

What are acetanilide and phenacetin?

Answer 6

metabolized by CYP1A2 to acetaminophen in vivo, but are too toxic – metabolic removal of acetate forms anilines that cause nephropathy, methemoglobinemia, and hemolytic anemia

Question 7

What are the 3 proposed mechanisms of acetaminophen?

Answer 7

• COX inhibitor – greater inhibition of prostaglandin biosynthesis by COX3 in CNS compared to periphery with other COX
• FAAH inhibitor
• acetaminophen metabolite as FAAH substrate

Question 8

How does acetaminophen act as a FAAH inhibitor?

Answer 8

• agonists of cannabinoid receptors bind cannabinoid (CB1) and vanilloid/capsaicin (TRPV1) receptors
• acetaminophen inhibits endocannabinoid metabolizing enzyme fatty acid amide hydrolase (FAAH) and raises level of endocannabinoids

Question 9

How does acetaminophen metabolite act as a FAAH substrate?

Answer 9

• acetaminophen to p-Aminophenol (PAP) by arylacetamide deacetylase
• p-Aminophenol (PAP) conjugation to arachidonic acid by FAAH forms AM404, which acts as agonist for cannabinoid and vanilloid receptors (PAP has analgesic activity, but is too toxic for therapeutic use)
• AM404 can also inhibit COX1 and COX2 activity – expected that COX inhibition occurs in brain regions where FAAH is highly expressed (both TRPV1 and cannabinoid CB1 receptor are found in brain regions with high expression of FAAH)

Question 10

What is the metabolic pathway of acetaminophen that can cause toxicity?

Answer 10

• metabolized primarily by sulfotransferase/ST (high affinity, low-capacity enzyme) to form sulfate adduct and UDP-glucuronosyltransferase/UGT (low affinity, high-capacity enzyme) to form glucuronide conjugate
• minor but significant product of both acetaminophen and phenacetin is N-hydroxy amide produced by CYP450 – hydroxyamide is converted to reactive toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI), which can produce nephrotoxicity and hepatotoxicity
• CYP inducers (ie. alcohol) can exacerbate pathway to NAPQI formation