NSAIDs Flashcards
What is the MOA for all NSAIDs? What is it used to treat primarily?
Involve disruption of prostanoid biosynthesis by inhibition of the CYCLOOXYGENASE (COX) enzyme
> Treatment of inflammation
Are NSAIDs lipophilic or hydrophilic? What is their key enzyme binding group?
Most NSAIDs are lipophilic. Possess a C02H group that acts as key enzyme binding group
What are the differences in how the body reacts when NSAIDs inhibit COX-1 or if NSAIDs inhibit COX-2
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
What are FIVE examples of non-steroidal NSAIDs?
- Salicylates
- Propionic Acids
- Aromatic Acetic Acids
- Oxicams
- Coxibs
What are the components in the active site of the COX isoforms (cox-1 and cox-2)? Briefly explain what they do.
- 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)
What is the difference between the structure of the active sites in COX-1 and COX-2?
COX-1: Two isoleucine residues
COX-2: Two smaller valine residues –> hydrophilic side pocket with certain hydrogen bonding residues
For COX-1;
A) What form does it represent
B) What is its role in the body?
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])
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
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
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.
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
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?
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
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?
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
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?
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
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?
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
