(6A) NSAIDs: Salicylates, Fenamates, Oxicams & COX-2 Inhibitors

What we talk about in NSIDS?

• Salicylates

• Fenamates

• Oxicams

• COX-2 Inhibitors

• Arylalkanoic Acids

Give me the Salicylates?

• Salicylic Acid

• Aspirin

Salicylic Acid

• Salicylic acid may appear in formulations and skin-care products.

• It is not the major oral anti-inflammatory agent being focused on here.

• Focus on aspirin/acetylsalicylic acid

At physiological pH, what is aspirin’s ionization?

• At physiological pH (after being absorbed), aspirin has a high ionized fraction (overwhelmingly in the negatively charged formed)

• professor estimated approximately 10,000:1 ionized : unionized (I/U)

Aspirin Mechanism

Serine –OH attacks the carbonyl of aspirin's acetoxy group

→ acetyl group transfers to serine

→ serine becomes acetylated

• salicylate anion is released

→ COX activity is inhibited.

• → COX-1 fully inhibited

  → COX-2 becomes very sluggish.

What is the difference between Aspirin and Naproxen?

• Aspirin = irreversible

  • It acetylates COX serine.

  • That is why its effect lasts.

• Naproxen = reversible

  • It only inhibits COX while it is bound; when it falls off, COX can work again.

Patient takes low-dose aspirin (81mg) + naproxen. What should they do?

• Take aspirin first

• let aspirin acetylate COX

• then take naproxen about 30–60 minutes later.

• If aspirin and naproxen are present together:

  Naproxen can competitively occupy the site → interfere with aspirin getting in and producing irreversible acetylation.

What do platelets use COX-1 for?

To produce TXA₂, which promotes platelet aggregation/clumping.

Why aspirin's platelet effect lasts so long

• Low-dose aspirin: COX-1 irreversibly inhibited → TXA₂ synthesis ↓

• Platelets:

  • Have no nucleus

  • therefore no DNA blueprint to make new COX-1

  • platelet must ultimately be replaced

Aspirin

duration?

about 4–6 hours.

Metabolism and Duration relationship

Fast metabolism → short duration
Slow metabolism → longer duration

Aspirin

Metabolism

• Aspirin → esterase → salicylic acid → Phase II metabolism

  • salicylic acid has much less anti-inflammatory activity

  • Then salicylic acid can undergo Phase II pathways::

    • Glycine conjugation at the carboxylic acid = major pathway

    • Glucuronidation at the carboxylic acid and/or phenol OH = minor pathways

COME BACK, DON’T GET:

Aspirin In-Vitro Decomposition

Aspirin contains an ester that can auto-hydrolyze during storage.

Aspirin In-Vitro Decomposition

Professor's practical signs:

Moisture / degradation

• Aspirin can break down and develop a vinegar smell.

• If it smells like vinegar:

  • Professor said to discard it.

  • It may not necessarily be toxic, but it will have much less anti-inflammatory/pain-relief activity.

Light exposure

• Aspirin may also discolor through formation of a quinone.

• So appearance changing away from bright white/toward discoloration can indicate decomposition.

What are the 2 types of Fenamates?

• Mefenamic Acid

• Meclofenamate

Who more potent: Fenamates or aspirin/naproxen?

• Fenamates shown > aspirin/naproxen in potency.

  • Fenamates have 2 separate aromatic rings + conjugation → greater potency.

    The nitrogen between the rings helps maintain that conjugation.

Which is more potent?

Meclofenamate > mefenamic acid

WHY is meclofenamate more potent?

Chlorines (Cl) do two important things:

1. Cl → lipophilicity ↑ → better distribution

AND

2. bulky ortho Cl groups → rings twist / become non-coplanar → better COX binding → potency ↑

Cl affects…

Cl affects POTENCY, not duration.