5. NSAIDs

NSAIDs mechanism

• Significance of selectivity

  • local pain and inflammation - COX-2 selective is beneficial for use b/c it would not inhibit normal basal levels of COX-1, which are important for protecting the stomach

Gastric acid/defense mechanisms

• How stomach acid is controlled and why some NSAIDs can irritate the stomach

1. Histamine increases stomach acid

   1. binds to H2 receptors in stomach cells and activates proton pumps, which releases H+ = more acid in the stomach

• this can be blocked by H2 Blockers, PPIs, Antacids

2. Prostaglandins help protect the stomach

   1. PGE₂ and PGI₂ - these reduce proton pump activity, lower stomach acid production, and help maintain healthy balance in the stomach

3. Why NSAIDs hurt the stomach

   1. COX is needed to make PGs

      1. COX → PGs → Less acid

   2. PGs are also involved in the production of mucin - protects the stomach

   3. NSAIDs are organic acids, so when released in the stomach, these organic acid contribute to acidity, and organic, so will be able to penetrate into cells of stomach

• these block COX enzyme leading to fewer PG production, so stomach loses its natural protection, acid production may increase, and lining of stomach becomes more vulnerable to irritation and ulcers

Prostanoid synthesis

• Prostanoids are a family of biologically active lipid mediators produced from arachidonic acid through the cyclooxygenase (COX) pathway.

  • Examples: PGE₂ PGI₂ TXA₂

Arachidonic acid bound to COX

Pharmacophore

• An acidic group - usually a carboxylic acid

• Lipophilic unsaturated region - benzene, aromatic rings, double bonds of hydrocarbons

  • Why? b/c NSAIDs mimic arachidonic acids, the natural substrate of the COX enzyme

• What makes acetylsalicylic acid (aspirin) a true NSAID

  • use its pharmacophore

• All of these treat pain but only aspirin is the true NSAID here because it has:

  • carboxylic acid

  • aromatic ring

• can inhibit COX enzymes, therefore:

  • pain relief, fever reduction, anti-inflammatory effects

• Acetaminophen has:

  • aromatic ring

  • carbonyl group

  • BUT no NSAID pharmacophore and weak/no peripheral COX inhibition, therefore it has

    • pain relief fever reduction, very little anti-inflammatory effect

Why NSAIDs can have different structures

Look at drugs like:

• Aspirin

• Ibuprofen

• Flurbiprofen

• Indomethacin

• Naproxen

They all look different.

But they all contain:

1. An acidic group

2. A lipophilic aromatic region

So they all satisfy the NSAID pharmacophore

note: nabumetone does not have a CO2H group

Ibuprofen - COX-1

• How NSAIDs bind COX

• Binds to the same site as arachidonic acid

• The COX enzyme has an amino acid called:

  • Arginine 120

    • Arginine is positively charged.

    • The NSAID carboxylate is negatively charged.

    • So they form a strong:

      • Ion-ion interaction

        • (-) NSAID ↔ (+) Arginine

        • This is the strongest binding interaction.

• Exam Pearl

  • Carboxylic acid = anchor

  • The acidic group grabs onto Arg120 and holds the drug in place.

• After the carboxylic acid anchors the drug:

  • The aromatic rings fit into a:

    • Hydrophobic pocket

    • A pocket lined with non-polar amino acids.

• So:

  • Acid group anchors

  • Aromatic rings fill the pocket

    • Together they block COX activity.

• Why Acidic NSAIDs Accumulate in Inflamed Tissue

  • Inflamed tissue has Lower pH (more acidic)

    • In acidic environments:

      • Carboxylic acids become more Neutral (uncharged); Neutral molecules cross membranes better.

  • Therefore NSAIDs enter inflamed tissue more easily.

  • This helps them concentrate where inflammation exists.

• Why NSAIDs bind albumin

  • NSAIDs are acidic and lipophilic

  • Albumin loves acidic, lipophilic drugs

    • Therefore NSAIDs are highly protein bound (often > 95%)

• Why warfarin interacts with NSAIDs

  • Warfarin also binds albumin strongly. If an NSAIDs displaces warfarin: more free warfarin = more bleeding

Why flubiprofen is more potent than ibuprofen

Ibuprofen has:

• One aromatic system

Flurbiprofen has:

• Two aromatic rings

More aromatic rings means:

• Larger molecule

• More contact/tighter binding with hydrophobic pocket

• Stronger binding

Therefore - More potency

Salicylates (sub-class)

• Contains

  • CO₂H attached directly to aromatic ring and a orthohydroxyl group or modified hydroxyl group

• these are OTC except Diflunisal

• Acidity of molecules

  • Diflunisal has pKa of ~3

    • most acidic

  • others are a little higher ~3.5

• the -sal is in the generic name to recall that these are salicylates

General SAR for salicylate NSAIDs

• aspirin being a prodrug of salicylic acid is controversial

What makes aspirin unique

• Aspirin = Acetyl group = Irreversible COX inhibition

• No acetyl group (salicylate) = only reversible inhibition.

• Aspirin is unique because its acetyl group covalently acetylates a serine residue in COX, causing irreversible inhibition of platelet COX-1 and long-lasting anti platelet effects for the life of the platelet (about 8–10 days).

• Why baby aspirin works

  • low dose aspirin taken daily:

    • continuously destroys COX in newly formed platelets

    • keeps thromboxane levels low

    • prevents clot formation

  • that’s why pts take 81 mg aspirin qd for prevention of MI, stroke, other thrombotic events

• Why does old aspirin smell like vinegar?

  • Aspirin + water -→ Salicylic acid + acetic acid (vinegar)

• Clinical pearl

  • Storage: Heat + moisture accelerates aspirin breakdown - hydrolysis

    • if aspirin smells strongly like vinegar, it is degrading

• Why does aspirin degrade itself?

  • carboxylic acid group can help catalyze its own hydrolysis - called self-catalyzed degradation

Aspirin metabolism

• how is aspirin converted and what is it converted to

• what are the different processes that eliminate salicylate acid (3)

• Toxicities (3)

• Conversion via hydrolysis: Aspirin → salicylate acid (still active, meaning it can still have effects on the body)

• The liver further metabolizes salicylate acid and want to make it easier to eliminate the drug from the body via oxidation:

  • CYP 450 enzymes add oxygen to different spots on the aromatic ring

• Glucuronidation - addn of glucuronic acid to salicylate acid makes the molecule more water soluble and easier to excrete in the urine

  • attaches to hydroxyl group or carboxylic acid

• Glycine conjugation - addn of glycine

  • main pathway for salicylate acid excretion

• Toxicity

  • one of the glucuronidation products called acyl glucuronide can be chemically reactive; this is NOT unique to aspirin, can also occur in other NSAIDs

  • Salicylate hypersensitivity reaction

  • Reye’s syndrome

    • pt may have suffered from viral infection (flu) and taking aspirin in that time can develop an autoimmune disease of brain and liver swelling

      • use of aspirin in young children is not recommended due to this

Fenamates - closely related to salicylates

General SAR for fenamate NSAIDs

Fenamate metabolsim

• Anywhere where there’s a benzylic methyl, it is a hot spot for cytochrome P450 metabolism

Acetic acids

• all have acetic acid portion except nobumatine

• Etodolac has a chiral center in the molecule

• Solindac and Diclofenac are associated with higher incidence of liver toxicity

  • Diclofenac structure is similar to acetaminophen

• Etodolac and diclofenac are COX-2 selective molecules

• All are Rx

  • but diclofenac can be purchased OTC (cream/gel)

General SAR for acetic acid NSAIDs

Sulindac and nabumetone are prodrugs

• Sulindac

  • Active form conversion: reduction of the sulfoxide to the sulfide; may also oxidize the sulfoxide all the way to the sulfone

• Nabumetone - does not have a carboxylic acid, it has a ketone

  • needs to be bioactived to the carboxylic acid

    • Active form conversion:

      • Oxidation: insert oxygen between the carbonyl and CH2 group

      • Hydrolysis occurs

      • Further oxidation occurs

      • Active carboxylic acid metabolite

CYP3A4 activates these prodrugs?

Propionic acids

• None are COX-2 selective

• All have the aromatic ring and propionic acid structure

General SAR for propionic acid NSAIDs

Oxicams

• these are enolic acids (acidic)

General SAR for oxicam NSAIDs

• meloxicam is COX-2 selective b/c:

  • the electronic of thiazole ring changing conformational preferences in the molecule

Coxibs (COX-2 Selective)

• these are purposefully designed to be COX-2 selective

General SAR for coxib NSAIDs

Coxib metabolism

• If Chloro or Fluoro group instead of methyl group, metabolism is not well achieved - had too long of a half life

COX-2 selective charatertics

NSAID Generalizations