NSAIDs

Question 1

What is the MOA for all NSAIDs? What is it used to treat primarily?

Answer 1

Involve disruption of prostanoid biosynthesis by inhibition of the CYCLOOXYGENASE (COX) enzyme

> Treatment of inflammation

Question 2

Are NSAIDs lipophilic or hydrophilic? What is their key enzyme binding group?

Answer 2

Most NSAIDs are lipophilic. Possess a C0₂H group that acts as key enzyme binding group

Question 3

What are the differences in how the body reacts when NSAIDs inhibit COX-1 or if NSAIDs inhibit COX-2

Answer 3

If NSAIDs inhibit Cox-1

• Less gastric-mucous forms
• HCL attacks gastric lining
• Gastric irritation results

If NSAIDs inhibit COX-2

• Less inflammatory PGs
• Less inflammation
• But COX-2 has a key role in vasculature tone –> may impact cardiac blood supply

Question 4

What are FIVE examples of non-steroidal NSAIDs?

Answer 4

1. Salicylates
2. Propionic Acids
3. Aromatic Acetic Acids
4. Oxicams
5. Coxibs

Question 5

What are the components in the active site of the COX isoforms (cox-1 and cox-2)? Briefly explain what they do.

Answer 5

• Hydrophobic entry channel
• Haem cofactor (acts as the primary catalytic site)
• Tyrosine residue (acts as a catalytic site)
• Arginine residue (functions as a cationic binding site)

Question 6

What is the difference between the structure of the active sites in COX-1 and COX-2?

Answer 6

COX-1: Two isoleucine residues

COX-2: Two smaller valine residues –> hydrophilic side pocket with certain hydrogen bonding residues

Question 7

For COX-1;

A) What form does it represent

B) What is its role in the body?

Answer 7

A)

• COX-1 represents a constitutive form i.e. continuously produced in vivo

B)

• Catalyses biosynthesis of key prostanoids needed for various vital bioprocesses (e.g. gastric mucosa secretion [PGE2/PGI2], platelet aggregation [TXA2], renal function [PGI2])

Question 8

For COX-2;

A) What form does it represent?

B) What is its role in the body

C) Why is it the principal biotarget for NSAIDs

Answer 8

A)

• Inducible isoform which is biosynthesised (stimulated by various cytokines) at injury and trauma sites

B)

• Serves as a major trigger in tissue inflammation with an indirect cytoprotective role
• COX-2 possesses NO GIT, blood or renal function

C)

• COX-2 represents the principal biotarget for NSAIDs due to its mediative role in inflammation and pain

Question 9

For Salicylates;

A) Why is it acidic

B) Does it inhibit cox-1 or cox-2? Is it reversible or competitive?

C) Why are there side effects of gastric ulceration and blood thinning?

D) How does aspirin differ from typical salicylates even though its a type of salicylate? Provide THREE ways it differs.

Answer 9

A)

• Due to the CO₂H group
• Possess a weakly acidic phenol

B)

Inhibits BOTH COX-1 and COX-2. Reversible and competitive.

C)

Selectively inhibits COX-1

D)

• Acts as a pseudo prodrug salicylic acid –> rapidly hydrolyzed in vivo by esterases
• Doesn’t possess a phenol
• IRREVERSIBLE suicide COX inhibition (100x more potent against COX-1 than COX-2) –> acts by acetylation of key serine residue OH group

Question 10

For Propionic Acids;

A) What is its structure? Why is it acidic?

B) Displays greater ……. than salicylates?

C) Does it inhibit cox-1 or cox-2? Is it reversible or competitive?

D) What does the methyl group do?

E) Most are available as racemate except for? What is the benefit of this? is S or R enantiomer more potent?

F) Are they known as profens?

Answer 10

A)

• AR (aromatic)-CH₃CH₂COOH
• All display acidic behavior due to a C0₂H group

B)

Displays greater lipophilicity than salicylates

C)
BOTH –> reversible competitive inhibitors of COX

• COX-1 selectivity like salicylates (expect Naproxen)

D)

Improves anti-inflammatory activity and reduces their toxicity vs salicylates

E)

• NAPROXEN –> (S)-enantiomer only
• S-enantiomer is the most potent form (fit better into cox active site)

F)

YES

Question 11

For Aromatic Acetic Acids;

A) What is their structure?

B) Does it inhibit cox-1 or cox-2? Is it reversible or competitive?

C) What is the most potent form?

D) What is an example of a prodrug?

E) What is not a true aryl acetic acid?

F) Which S-enantiomer is bioactive?

G) What is the COX2:COX1 selectivity?

H) Which is the only NSAID avaliable as an IM injection?

Answer 11

A)

• Ar-CH₂CO₂H based drugs (aryl and heteroaryl derivatives of acetic acid)

B)

NON-SELECTIVE COX INHIBITORS

C)

Z-Geioisomer of Sulindac is most potent

D)

• Sulindac is a prodrug –> requires invivo bioreduction

E)

• Etodolac is NOT a true aryl acetic acid –> displays COX-2 selectivity

F)

• Etodolac is available as a racemate (R form) but only the (S) enantiomer is bioactive –> similar to profens

G)

• COX2: COX1 selectivity of 3:1

H)

• Ketorolac

Question 12

For Oxicams;

A) What is its structure

B) What structural group does it have that others NSAIDs typically don’t

C) Does it inhibit cox-1 or cox-2? Is it reversible or competitive?

D) Why does meloxicam display greater COX-2 selectivity?

Answer 12

A)

• 4-hydroxybenzothiazine based drugs

B)

Possess a mildly acidic enol group, non-carboxylic acid-containing NSAID

C)
COMPETITIVE COX INHIBITORS

D)

• Better COX-2 fit and interaction of sulfonamide unit with hydrophilic based drugs

Question 13

For Coxibs;

A) Does it inhibit cox-1 or cox-2? Is it reversible or competitive?

B) Mickey mouse structure?

C) COX2: COX 1 selectivity?

D) Which condition is it the leading therapeutic treatment of?

E) What are some factors that affect anti-inflammatory potency and COX2: COX1 selectivity?

Answer 13

A)

COX-2 INHIBITOR DRUGS

> hydrogen bonds to hydrophilic regions of COX-2

B)

• ortho-DIARYL 5-MEMBERED HETEROCYCLES

C)

• COX2:COX1 = 8:1 (very little gastric irritation as a consequence)

D)

• Treatment of arthritis

E)

• ring substitution on the 2nd non-sulfonamide aryl ring (at c-2 and/or 4 positions) can affect both anti-inflammatory potency and COX2: COX-1 selectivity
• Sulfonyl group vital for COX-2 activity

See attached image