MedChem NSAIDs Study Guide

Acetaminophen (Not technically an NSAID as it lacks anti-inflammatory effects)

Anilides

- Aspirin

- Diflunisal

- Salsalate

Salicylates

- Indomethacin

- Sulindac

- Tolmetin

- Diclofenac

- Nabumetone

- Ketorolac

Aryl Acetic Acids

- Ibuprofen

- Naproxen

- Ketoprofen

- Fenoprofen

- Flurbiprofen

- Oxaprozin

- Etodolac

Aryl Propanoic Acids ("Profens")

- Piroxicam

- Meloxicam.

Oxicams (Enolic Acids)

Celecoxib

Selective COX-2 Inhibitors.

- Phospholipase A2 releases Arachidonic Acid from membrane phospholipids .

- Cyclooxygenase (COX) converts Arachidonic Acid into Prostaglandin G2 (PGG2) and PGH2

-PGH2 is converted into prostaglandins (PGE2, PGF2, PGI2) and Thromboxanes (TXA2).

Prostaglandin Biosynthesis

Inhibit Cyclooxygenase (COX) enzymes to shut down the inflammatory pathway

NSAID MOA

Inhibits platelet aggregation via acetylation of COX (irreversible).

Aspirin specific MOA

Drug enters epithelial cells and inhibits COX-1

Mechanisms of GI Toxicity Primary Cause

- Decreased blood circulation to stomach mucosa.

- Increased permeability of epithelial cells.

- Decreased mucus buffer.

- Increased gastric acid secretion

4 specific Mechanisms of GI Toxicity

Many _______ are acidic (carboxylic acids), causing direct irritation (H+ accumulation) alongside the systemic inhibition of protective prostaglandins

NSAIDs

- The simplest active agent is the salicylic acid anion.

- The carboxylic acid is necessary, and the hydroxyl group must be adjacent (ortho) to it.

- Diflunisal

Salicylates SAR

______ increase lipophilicity and acidity, which increases potency

Difluoro groups

Optimal separation of the carboxylic acid from the aromatic ring is one methylene unit.

Aryl Acetic Acids SAR

- Indole ring

- Chlorine substitution reduces metabolism and increases half-life (4-5 hr).

Indomethacin

Short half-life (1 hr) due to rapid oxidation of the toluene methyl group to an inactive carboxylic acid.

Tolmetin

- Addition of one methylene unit

- potent analgesic (6x Indomethacin)

- preferential COX-2 inhibitor

Diclofenac

- Cyclic analogue of tolmetin

- very high potency (severe pain)

- highest risk of GI effects.

Ketorolac

- substitution of the acetic acid group increases potency

- specifically, the S-(+) enantiomer usually holds the activity .

Aryl Propanoic Acids ("Profens") SAR

Activity resides in S-(+)-isomer; metabolized by omega-1 oxidation

Ibuprofen

- Naphthalene ring

- 12x more potent than aspirin

- longer half-life (12 hr) due to O-demethylation metabolism.

Naproxen.

Fluorine atom increases acidity and potency (500x more potent than aspirin).

Flurbiprofen

- Exception to the rule

- acid is separated by two methylene units

- longest half-life (58 hr)

- once-daily dosing.

Oxaprozin

- Do not contain a carboxylic acid (enolic acid instead)

- 4-hydroxy-1,2-benzothiazine structure.

Oxicams SAR

- Thiazole ring replaces pyridine

- preferential COX-2 inhibitor

Meloxicam

- A sulfonamide group replaces the carboxylic acid.

- The sulfonamide binds to a specific side pocket in the COX-2 active site (Arg513) that is not accessible in COX-1.

Selective COX-2 Inhibitors SAR

- Reference Standard for potency

- Non-selective

- Short (hydrolyzes rapidly)

Aspirin

- Good potency

- Non-selective

- Short t 1/2 (1 hr)

Tolmetin.

- More potent than aspirin

- Non-selective

- Short t 1/2 (1 hr)

Ibuprofen.

- 6x potency of Indomethacin

- COX-2 > COX-1

- Short t 1/2 (1 hr)

Diclofenac.

- High Potency (Severe pain)

- COX-1 > COX-2

- Short t 1/2

Ketorolac

- One of most potent

- Non-selective

- Moderate t 1/2 (4-5 hr)

Indomethacin

- 12x potency of Aspirin

- Non-selective

- Moderate t 1/2 (12 hr)

Naproxen

- High Potency

- COX-2 > COX-1

- Long t 1/2 (20 hr)

Meloxicam.

- High Potency

- Non-selective

- Long t 1/2 (38 hr)

Piroxicam

- Less potent than Ibuprofen

- Non-selective

- Longest t 1/2 (58 hr)

Oxaprozin

- Analgesic

- Highest COX-2

Celecoxib

- Ketorolac

- Indomethacin

- Piroxicam.

Highest GI toxicity Risk

- Nabumetone (non-acidic prodrug)

- COX-2 inhibitors (Celecoxib)

Lower GI toxicity Risk

- Hepatotoxicity

- Occurs at high doses/overdose

Acetaminophen (Anilides) toxicity

- It is metabolized in the liver to a toxic intermediate (via N-oxidation) which depletes liver glutathione (GSH).

- GSH normally detoxifies the drug; when depleted, liver damage occurs.

- Para-hydroxy group reduces methemoglobin toxicity compared to acetanilide

Acetaminophen (Anilides) toxicity mechanism

- Cardiovascular Toxicity

- Severe cardiovascular events led to the removal of Rofecoxib (Vioxx), Valdecoxib (Bextra), and Lumiracoxib from the market.

Selective COX-2 Inhibitors toxicity

- Sulindac

- Nabumetone

prodrugs

The sulfoxide must be reduced to the active sulfide form

Sulindac

A non-acidic ketone that must be metabolized to the active acetic acid form (loses 2 carbons).

Nabumetone

- Celecoxib

- Contains a sulfonamide group, creating a risk for patients with sulfa allergies.

Sulfonamide Hypersensitivity

- Metabolized to glucuronide and sulfate conjugates (safe)

- N-oxidation creates the toxic intermediate (unsafe)

Acetaminophen

- Toluene oxidation (methyl group on ring becomes carboxylic acid) Inactivates drug

- Short half-life.

Tolmetin

Chlorine on the ring blocks metabolism, extending half-life

Indomethacin

Omega-1 oxidation (oxidation at the end of the isobutyl chain).

Ibuprofen

O-demethylation (removal of the methyl group on the oxygen).

Naproxen

Ketone reduction (the ketone C=O becomes an alcohol C-OH).

Ketoprofen

Metabolized by CYP2C9 (specifically via oxidation of methyl groups or pyridine rings).

Piroxicam / Meloxicam / Celecoxib

Oxidative cleavage (loses 2 carbons) to become the active acetic acid.

Nabumetone (prodrug)