3 & 4 - NSAIDs Flashcards
What are the side effects of NSAIDs?
- GI irritation and bleeding
- Platelet dysfunction
- Kidney damage
- Bronchospasm
What are the therapeutic actions of NSAIDs?
1) Inhibit COX-1
2) Inhibit COX-2
When does COX-1 function?
On an “as-needed” basis
When is COX-2 over-expressed?
During injury, inflammation, and infection
What is cyclooxygenase the rate limiting enzyme for?
Biosynthesis of pro-inflammatory prostaglandins
What are the functions of various prostaglandins?
- PGD2, PGE2, PGI2, and PGF2a = pain transmission, inflammation, and fever
- TXA2 and PGI2 = modulation of platelet activity
- PGE2 and PGI2 = gastric acid secretion/cytoprotection
- PGE2 = renal blood flow
Prostaglandins are ____-like molecules
Lipid
In what part of the process do NSAIDs inhibit cyclooxygenase?
During the rate-limiting oxidative cyclization of arachidonic acid into hydroperoxy-endoperoxide PGG2, which is reduced to PGH2
What is the key intermediate needed for all prostaglandin biosynthesis?
PGH2
What are the key steps of biosynthesis of prostaglandins?
Phospholipids -> arachidonic acid -> PGG2 -> PGH2 -> PGD2/ PGE3/ PGF2a/ PGI2/ thromboxanes
What would blockade of PGH2 production cause?
Prevention of the down-stream production of resulting prostaglandin analogues
What does the 2 mean in prostaglandin E2?
of double bonds in the chain
What family do prostanoids and thromboxanes belong to?
Eicosanoids
How is arachidonic acid produced?
From linoleic and linolenic acid from plants through the human diet
What is important about the structure of prostaglandins?
Contain a bicyclic endoperoxide ring system
What do alpha and beta mean w/ respect to stereochemistry of functional groups?
- Alpha = down (into page)
- Beta = up (out of page)
Which prostaglandins are used in glaucoma?
Latanoprost and fluprostenol (23 and 49)
Why is a C1 modification for prostaglandins bad? What will a modification cause?
What are the exceptions to this?
- Carboxylic acid interacts w/ arginine residue in transmembrane domain 7 (through H bonding or ionic bonds)
- Modification will cause dramatic decrease in potency
- Exceptions are sulprostone and enprostil, which have a phenoxy substituent
What is important about the 11 alpha-hydroxy of a prostaglandin?
Very important for potency
Modification of ____ of a prostanoid is the primary method to increase potency
w-tail (omega tail)
Which functional groups of a prostaglandin are most important for agonism?
- Configuration of 15-hydroxyl group is most critical
- Followed by 1-carboxylic acid, then 11 alpha-hydroxy group, and chirality at C8
What is important about the double bonds of a prostanoid?
Favourable to have them in conjugation
What is the half life of prostanoids? Why?
Short b/c susceptible to rapid degradation
What substitutions can be made to a prostanoid to make it more resistant to chemical and metabolic degradation?
- Methylation at C15 or C16 to reduce oxidation
- Esterification of carboxylic acid (prodrug)
- Hydrophobic substituents (phenyl) replacing alkyl chains
What is the half life of thromboxanes? Why?
60 seconds (very short) b/c bicyclic oxane-oxetane ring system is unstable and susceptible to deactivation by hydrolysis
What does a prostacyclin contain?
Labile exocyclic (outside of ring) enol-ether functional group that is very susceptible to hydrolysis, but can be prevented by replacing oxygen w/ carbon to prevent hydrolysis
What are advantages to selective COX-2 inhibitors?
- Inhibition of COX-2 may reduce acute inflammation
- Allowing normal function of COX-1 continues normal kidney function and mucosal lining of GI tract
What do non-selective COX inhibitors (like ASA) do at high doses?
Irreversibly inhibit both COX-1 and COX-2, which can lead to kidney and GI adverse events
What functional groups do you need to watch out for w/ prostanoids?
Those that can undergo oxidation
What are the functions of ASA at low doses?
Antiplatelet and antipyretic
What is the effect of a daily low dose (81 mg) of ASA?
Reduces platelet aggregation by altering the prostanoid balance in systemic blood to PGI2 > TxA2, giving cardioprotective effects
What is the function of ASA at high doses?
Anti-inflammatory, irreversible
Is ASA a prodrug?
- Yes, the active metabolite is salicylic acid
- ASA is an irreversible inhibitor, SA is reversible
When are aminosalicylic acids used?
In inflammatory bowel disease and Crohn’s disease
What is the difference between ibuprofen and naproxen?
- Ibuprofen is a racemate mixture
- Naproxen is only the more active (S)-isomer
What is the main mechanism of metabolism of NSAIDs?
Glucuronidation of carboxylic acid
What is the antipyretic mechanism of acetaminophen?
Lowers PGE2 concentration in CNS, lowering hypothalamic set point in thermoregulatory center
What is the analgesic mechanism of acetaminophen?
- Not well understood
- May be highly selective for COX-2
- Active metabolite NAPQI may act in spinal cord and suppress signal transduction and decrease pain
- May inhibit COX-3 (COX-1 variant), depleting stores of GSH
What are disadvantages to selective COX-2 inhibitors?
Give rise to cardiotoxicity outcomes in susceptible px (heart attack, stroke)
Does TxA2 or PGI2 need to be in greater concentration to promote platelet aggregation?
TxA2 > PGI2
Why is celecoxib (Celebrex) still on the market as a selective COX-2 inhibitor?
- Has the poorest selectivity of the group, and greater selectivity = more cardiotoxic
- Is bioactivated by CYP3A4 to active metabolite (prodrug)
What is the 15-hydroxyl group of PGE2 critical for?
EP1 agonism
What are the 7 key structural features of a non-selective COX inhibitor?
1) Must have ionizable acid group and aromatic group for activity
2) 2nd non-coplanar aromatic ring increases potency and bonding interactions
3) Limiting the number of possible conformers increases potency and decreases rotatable bonds
4) 2-atom separation between anionic charge and aromatic ring is optimal
5) Increasing distance to 3-4 carbons decreases potency
6) Addition of methyl at first carbon increases potency and introduces chiral center
7) S-isomers are more potent
