MSK 01 and 04: NSAIDs Flashcards
Describe the actions of NSAIDs.
have both peripheral actions (anti-inflammatory, analgesic) and central effects (analgesic, antipyretic)
What is the mechanism of action of NSAIDs?
inhibit biosynthesis of prostaglandins by competitive antagonism of COX1 and COX2 catalytic site
What is the mechanism of action of acetylsalicylic acid (ASA)?
- non-competitive inhibitor of COX
- irreversible acetylation of serine in catalytic site of COX (both COX1 and 2) enzyme mediates anti-prostaglandin action
What is the main metabolite of NSAIDs?
salicylate
- weak anti-inflammatory, antipyretic, and analgesic effects as a competitive COX antagonist (reduces prostaglandin synthesis)
- may also down regulate COX2 gene transcription
- inhibit platelet aggregation by targeting COX1 in cells and preventing formation of TXA2
What are the major deleterious effects of NSAIDs and ASA? (4)
- ↑ blood pressure
- ↓ renal function – prostaglandins regulate renal blood flow and promote Na+ excretion (COX1 and COX2)
- GI ulceration (COX1) – PGE2 promotes ↓ HCl and ↑ GI mucous production
- anti-platelet action – slight ↑ in bleeding time, except for ASA
What is the mechanism of action of celexocib?
- COX2 selective NSAID
- inhibits biosynthesis of prostaglandins by blocking COX2 with less effect on COX1 (dose related)
- not very selective (10-20x more selective for COX2), high dose celecoxib loses its selectivity for COX2
What are the adverse effects of celecoxib?
- similar or greater incidence of cardiovascular and renal side effects
- at lower doses, decreased ulcer risk and no effect on platelet aggregation
What is gastric damage caused by NSAIDs due to?
in part to acidity of carboxylate functionality, and in part to COX-1 inhibition
Compare salicylic acid and ASA.
- pseudo-6-membered ring in SA stabilizes deprotonated/ionized form
- pseudo-6-membered ring of ASA stabilizes protonated form
What is the mechanism of action of aspirin?
- COX inhibition
- the only NSAID that covalently modifies COX by acetylating Ser530 (COX-1)/Ser516 (COX-2), which blocks COX active site and interfere with arachidonate binding
- much more potent against COX-1 than COX-2
What are aryl alkanoic acid NSAIDs?
contain acetic acid or proprionic acid attached to aromatic or heteroaromatic group
Which acetic acid derivatives exhibit more COX1 selectivity?
indomethacin
Which acetic acid derivatives exhibit more COX2 selectivity?
- Z-sulindac
- sulindac sulfide
- diclofenac
- etodolac
Describe the structural and functional features of diclofenac.
o-Chloro groups force twisting – effect important for COX binding
What is nabumetone?
- naphthylalkanone derivative
What is the mechanism of action of nabumetone?
- non-selective COX-1 and COX-2 inhibitor
- converted to its active metabolite 6-MNA by liver enzyme CYP3A4
What are the advantages of nabumetone? (2)
- reduces possibility of GI side effects commonly associated with acidity of NSAIDs (no primary insult of GI tract)
- ineffective as COX-1 inhibitor in gastric mucosa (no secondary insult of GI tract)
Compare the potency of aspirin, diclofenac, and nabumetone?
aspirin < nabumetone < diclofenac
What are some proprionic acid derivatives?
- flurbiprofen
- ketoprofen
- naproxen
- ibuprofen
Describe the structure of proprionic acid derivatives.
- pharmacological activity resides in S(+) enantiomer, but most drugs are marketed as racemic
- epimerization of R(-) to S(+) enantiomer occurs rapidly in vivo
What is the mechanism of action of proprionic acid derivatives?
exhibit mostly COX-1 selectivity
Compare proprionic acid NSAIDs to acetic acid NSAIDs.
generally less acidic due to modest EDG effect of methyl group
What is ketorolac?
pyrrolizine carboxylic acid derivative
What is ketorolac structurally similar to?
- indomethacin
- ketoprofen
What is the mechanism of action of ketorolac?
- high degree of selectivity toward COX-1 over COX-2
- primarily for analgesic activity – similar to centrally acting analgesics (widely accepted as alternative to narcotic analgesia)
What are oxicams?
- enolic class of NSAIDs generally indicated for long-term use in rheumatoid arthritis and osteoarthritis
- unusually acidic compounds
What are some oxicams?
- piroxicam
- meloxicam
- tenoxicam
What is the mechanism of action of oxicams?
- highly potent
- exhibits selectivity toward COX-2 over COX-1
What occurs at the R1 position of oxicams?
N-heterocylic carboxamides are more acidic than corresponding N-aryl carboxamides
What is the acidity of oxicams due to?
stabilization of enolate anion by adjacent heterocyclic nitrogen atom through formation of two tautomers
- tautomers reveal anion stabilization by 2 pseudo-6-membered rings
What is the general idea behind COX2 selectivity?
provide therapeutic advantage over older NSAIDs by reducing inflammatory response (COX-2) and not interfering with GI-protective functions of COX-1
Describe the structure of selective COX2 inhibitors compared to other NSAIDs.
contain sulfonamide, sulfonyl, or related group in place of carboxylic acid group
What were selective COX2 inhibitors designed to do?
take advantage of larger substrate binding site of COX-2 as compared to COX-1
- COX-1 has Ile at position 523 in active site that restricts access to large rigid substrates
- COX-2 has Val at same position, which is smaller by one methyl group
- when selective COX-2 inhibitors are docked onto COX-1, sulfonamide/sulfonyl groups display repulsive interaction with Ile523, but not with smaller Val509 in COX-2
- these inhibitors fit into, and interact with, binding site of COX differently than other NSAIDs
What is the apparent consequence of selective COX2 inhibition?
significant reduction in production of prostacyclins (PGI2 suppression can cause elevated BP, accelerated atherogenesis, etc.)
- whereas COX-1 production of TXA2 (inducer of platelet aggregation) is unaffected
