Aspirin: Acetylsalicylic Acid

• Aspirin is a NSAID that belongs to the salicylic acid structural class
• Commonly prescribed for antipyretic, analgesic, and anti-inflammatory effects

History

• Ancient Greeks used willow leaves and meadowsweet for fever
• Salicin, a precursor to salicylic acid, was found in these plants
• Salicylic acid was used to treat arthritis in the early 1800s
  • Had poor patient tolerance due to taste and gastric side effects
• In 1899, Felix Hoffman at Bayer Pharmaceuticals synthesized aspirin from salicylic acid.

Acetylsalicylic Acid

• Hoffman added an acetyl group to salicylic acid, which created acetylsalicylic acid, or aspirin
• Modification caused it to irreversibly inhibit cyclooxygenase (COX) enzymes by acetylation
  • Most other NSAIDs inhibit cyclooxygenase enzymes by competing with the enzyme’s substrates for access to the active site

Acetylation

• Aspirin transfers its acetyl group to an amino acid residue in the active site of COX enzymes
  • Acetylates serine 529 in COX-1
  • Acetylates serine 516 in COX-2
• Serine residues are homologous, having the same relative position and function in the active site
  • Difference in number is due to slight variations in the amino acid sequence of the two enzymes
• An oxygen atom attacks the carbonyl on aspirin and is acetylated, converting aspirin into salicylic acid
• Acetylation nullifies the nucleophilicity of the hydroxyl group in the serine residue
  • Alters the structure of the active site, rendering the enzyme permanently ineffective

Irreversible Inhibition

• Irreversible inhibition of COX enzymes causes body to create new enzymes before the effect of aspirin wears off

Blood Clotting

• Effective in preventing blood clotting at very low doses
• Prostaglandins are produced in blood platelets and epithelial cells lining of blood vessels
  • Important for blood clotting activity
• Cyclooxygenase enzymes in blood platelets generate TxA2 (pro-clotting prostaglandin)
• Cells in blood vessels generate PGI2 (anti-clotting prostaglandin)
• Platelets lack a nucleus so cannot generate new RNA transcripts for protein production
  • Inhibited COX enzymes prevent platelets from generating pro-clotting prostaglandins for their 8-9 day lifespan
• Cells lining blood vessels continually generate new COX enzymes, thus can still generate anti-clotting prostaglandins
  • Shift causes blood thinning effects
• COX enzymes in platelets are acetylated within the portal vein
  • Carries blood from the gut (aspirin absorption location) to the liver (where aspirin is metabolized into salicylic acid)

Aspirin-Triggered Lipoxins (ATLs)

• Acetylation of cyclooxygenase-2 by aspirin leaves certain enzyme functions intact
• ATLs such as 15-epi-lipoxin-A4 are created
  • Epimer of a lipoxin, differing in the stereochemistry of one chiral center
  • Has potent anti-inflammatory effects and likely increases aspirin’s anti-inflammatory activity

Uses & Side Effects

• Potent and clinically important NSAID for the treatment of fever and pain
• Low doses treat heart disease or patients who have had a stroke
• 10-25% of people with asthma have worsened symptoms with aspirin use
• Has been associated with Reye’s syndrome
  • Primarily occurs in young people
  • Characterized by swelling of the liver and brain
• Due to this association, aspirin is not used in children, or young adults with a virus-induced fever.
• Acetaminophen (Tylenol) has not been implicated in Reye’s syndrome and has less significant gastric side effects
  • It is the drug of choice for the treatment of fever in children and young adults