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Medicinal Chemistry - Winter > 3 & 4 - NSAIDs > Flashcards

3 & 4 - NSAIDs Flashcards

1
Q

What are the side effects of NSAIDs?

A
  • GI irritation and bleeding
  • Platelet dysfunction
  • Kidney damage
  • Bronchospasm
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2
Q

What are the therapeutic actions of NSAIDs?

A

1) Inhibit COX-1

2) Inhibit COX-2

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3
Q

When does COX-1 function?

A

On an “as-needed” basis

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4
Q

When is COX-2 over-expressed?

A

During injury, inflammation, and infection

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5
Q

What is cyclooxygenase the rate limiting enzyme for?

A

Biosynthesis of pro-inflammatory prostaglandins

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6
Q

What are the functions of various prostaglandins?

A
  • 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
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7
Q

Prostaglandins are ____-like molecules

A

Lipid

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8
Q

In what part of the process do NSAIDs inhibit cyclooxygenase?

A

During the rate-limiting oxidative cyclization of arachidonic acid into hydroperoxy-endoperoxide PGG2, which is reduced to PGH2

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9
Q

What is the key intermediate needed for all prostaglandin biosynthesis?

A

PGH2

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10
Q

What are the key steps of biosynthesis of prostaglandins?

A

Phospholipids -> arachidonic acid -> PGG2 -> PGH2 -> PGD2/ PGE3/ PGF2a/ PGI2/ thromboxanes

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11
Q

What would blockade of PGH2 production cause?

A

Prevention of the down-stream production of resulting prostaglandin analogues

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12
Q

What does the 2 mean in prostaglandin E2?

A

of double bonds in the chain

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13
Q

What family do prostanoids and thromboxanes belong to?

A

Eicosanoids

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14
Q

How is arachidonic acid produced?

A

From linoleic and linolenic acid from plants through the human diet

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15
Q

What is important about the structure of prostaglandins?

A

Contain a bicyclic endoperoxide ring system

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16
Q

What do alpha and beta mean w/ respect to stereochemistry of functional groups?

A
  • Alpha = down (into page)

- Beta = up (out of page)

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17
Q

Which prostaglandins are used in glaucoma?

A

Latanoprost and fluprostenol (23 and 49)

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18
Q

Why is a C1 modification for prostaglandins bad? What will a modification cause?
What are the exceptions to this?

A
  • 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
19
Q

What is important about the 11 alpha-hydroxy of a prostaglandin?

A

Very important for potency

20
Q

Modification of ____ of a prostanoid is the primary method to increase potency

A

w-tail (omega tail)

21
Q

Which functional groups of a prostaglandin are most important for agonism?

A
  • Configuration of 15-hydroxyl group is most critical

- Followed by 1-carboxylic acid, then 11 alpha-hydroxy group, and chirality at C8

22
Q

What is important about the double bonds of a prostanoid?

A

Favourable to have them in conjugation

23
Q

What is the half life of prostanoids? Why?

A

Short b/c susceptible to rapid degradation

24
Q

What substitutions can be made to a prostanoid to make it more resistant to chemical and metabolic degradation?

A
  • Methylation at C15 or C16 to reduce oxidation
  • Esterification of carboxylic acid (prodrug)
  • Hydrophobic substituents (phenyl) replacing alkyl chains
25
Q

What is the half life of thromboxanes? Why?

A

60 seconds (very short) b/c bicyclic oxane-oxetane ring system is unstable and susceptible to deactivation by hydrolysis

26
Q

What does a prostacyclin contain?

A

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

27
Q

What are advantages to selective COX-2 inhibitors?

A
  • Inhibition of COX-2 may reduce acute inflammation

- Allowing normal function of COX-1 continues normal kidney function and mucosal lining of GI tract

28
Q

What do non-selective COX inhibitors (like ASA) do at high doses?

A

Irreversibly inhibit both COX-1 and COX-2, which can lead to kidney and GI adverse events

29
Q

What functional groups do you need to watch out for w/ prostanoids?

A

Those that can undergo oxidation

30
Q

What are the functions of ASA at low doses?

A

Antiplatelet and antipyretic

31
Q

What is the effect of a daily low dose (81 mg) of ASA?

A

Reduces platelet aggregation by altering the prostanoid balance in systemic blood to PGI2 > TxA2, giving cardioprotective effects

32
Q

What is the function of ASA at high doses?

A

Anti-inflammatory, irreversible

33
Q

Is ASA a prodrug?

A
  • Yes, the active metabolite is salicylic acid

- ASA is an irreversible inhibitor, SA is reversible

34
Q

When are aminosalicylic acids used?

A

In inflammatory bowel disease and Crohn’s disease

35
Q

What is the difference between ibuprofen and naproxen?

A
  • Ibuprofen is a racemate mixture

- Naproxen is only the more active (S)-isomer

36
Q

What is the main mechanism of metabolism of NSAIDs?

A

Glucuronidation of carboxylic acid

37
Q

What is the antipyretic mechanism of acetaminophen?

A

Lowers PGE2 concentration in CNS, lowering hypothalamic set point in thermoregulatory center

38
Q

What is the analgesic mechanism of acetaminophen?

A
  • 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
39
Q

What are disadvantages to selective COX-2 inhibitors?

A

Give rise to cardiotoxicity outcomes in susceptible px (heart attack, stroke)

40
Q

Does TxA2 or PGI2 need to be in greater concentration to promote platelet aggregation?

A

TxA2 > PGI2

41
Q

Why is celecoxib (Celebrex) still on the market as a selective COX-2 inhibitor?

A
  • Has the poorest selectivity of the group, and greater selectivity = more cardiotoxic
  • Is bioactivated by CYP3A4 to active metabolite (prodrug)
42
Q

What is the 15-hydroxyl group of PGE2 critical for?

A

EP1 agonism

43
Q

What are the 7 key structural features of a non-selective COX inhibitor?

A

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

Medicinal Chemistry - Winter (15 decks)

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