L18 & 19 - NSAIDs

Question 1

Explain how arachidonic acid is released from the membranes

Answer 1

Released from membrane phospholipids by phospholipase A2 (PLA-2)

Question 2

What is the physiological effect of PGE-2 on blood vessels?

Answer 2

dilation

Question 3

What is the physiological effect of PGF-2a on blood vessels?

Answer 3

constriction

Question 4

What is the physiological effect of PGI-2 on blood vessels?

Answer 4

dilation

Question 5

What is the physiological effect of TXA-2 on blood vessels?

Answer 5

constriction

Question 6

What is the physiological effect of PGI-1 on platelets?

Answer 6

inhibition of aggregation

Question 7

What is the physiological effect of TXA-2 on platelets?

Answer 7

promotion of aggregation

Question 8

What is the physiological effect of PGE-2 on bronchi?

Answer 8

dilation

Question 9

What is the physiological effect of PGF-2a on bronchi?

Answer 9

constriction

Question 10

What is the physiological effect of PGE-2 on the uterus?

Answer 10

oxytocic dilation

Question 11

What is the physiological effect of PGF-2a on the uterus?

Answer 11

oxytocic constriction

Question 12

List the end products of the cyclooxygenase pathways

Answer 12

Prostaglandins (“PG”)
Thromboxanes (“TX”)

Question 13

List the end products of the lipoxygenase pathways

Answer 13

Leukotrienes
Also - HPETEs, Lipoxins

Question 14

List the effects of COX-1 inhibition

Answer 14

GI effects
- Stomach irritation & ulceration
- Blockade of platelet aggregation
- Inhibition of uterine motility
- Inhibition of PG-mediated renal function
- Hypersensitivity reactions

Question 15

List the effects of COX-2 inhibition

Answer 15

• Pain relief
• Elevated blood pressure
• Accelerated atherogenesis

Question 16

Describe Alprostadil

Answer 16

a therapeutic prostaglandin

• PGE-1
• Relaxes smooth muscles and expand blood vessels
• Used for erectile dysfunction by injection or as a suppository

Question 17

Describe misoprostol

Answer 17

a therapeutic prostaglandin

• PGE-1 derivative
• Cytoprotective
• Prevents peptic ulcer, terminates early pregnancy in combination with mifepristone

Question 18

Describe latanoprost

Answer 18

a therapeutic prostaglandin

• topically active PGF-2a derivative (prodrug)
• constricts blood vessels
• used in ophthalmology to treat high pressure inside eye (ex. glaucoma)

Question 19

Describe prostacyclin

Answer 19

a therapeutic prostaglandin

• PGI-2
• Powerful vasodilator, inhibitor of platelet aggregation
• Used to treat pulmonary arterial hypertension by IV injection or inhalation
  (shouldn’t be used with anticoagulants)

Question 20

List the pharmacological activities of NSAIDs

Answer 20

Anti-inflammatory
Analgesic → pain killing
Antipyretic → fever suppressant

Question 21

Explain the mechanism of action of NSAIDs

Answer 21

Inhibition of prostaglandin endoperoxide H synthase (PGHS or COX), which catalyzes the formation of prostaglandins
(Many NSAIDs inhibit both COX-1 and COX-2)

Question 22

Explain the mechanism of gastric bleeding caused by NSAIDs

Answer 22

• Primary insult → acidity of many NSAIDs
• Secondary insult → Inhibition of synthesis of cytoprotective prostaglandins (PGEs) in gastric mucosa
• There is also an inhibition of platelet aggregation → causes increased tendency of bleeding

Question 23

Explain the mechanism of the inhibition of blood coagulation by aspirin

Answer 23

Irreversible inhibition of platelet COX-1 and the consequent reduced formation of thromboxane

Question 24

What is Reye’s syndrome?

Answer 24

• A rare, acute, life-threatening condition characterized by vomiting, delirium, and coma
• Brain damage is common in survivors

Question 25

What is one of the causes of Reye's syndrome?

Answer 25

giving salicylates (aspirin) to children who have had the chicken pox or flu

Question 26

Who should aspirin NOT be given to?

Answer 26

anyone under the age of 12 who has a fever

Question 27

Explain the main cause of drug interactions of NSAIDs

Answer 27

NSAIDs compete with other drugs for serum albumin binding sites (ex oral anticoagulants)

Question 28

List the classes of NSAIDs

Answer 28

Salicylates Arylacetic acids Arylpropionic acids Non-carboxylate NSAIDs COX-2 selective NSAIDs

Question 29

Explain the role of α-methyl group in the structure-activity relationship of arylpropionic acids

Answer 29

The α-Methyl group enhances it activity and reduces many side effects

Question 30

Describe the difference in the mechanism of action of acetaminophen from that of NSAIDs

Answer 30

It does not inhibit arachidonic acid binding to PGHS

Question 31

What is the mechanism of action of acetaminophen?

Answer 31

- Prevents PGH synthase activity by scavenging for Peroxynitrite, the major oxidant for PGH synthase activity in the CNS - In inflammation, high concentrations of peroxides are present, and acetaminophen scavenging is overwhelmed

Question 32

List NSAIDs that are prodrugs

Answer 32

Sulindac Nabumetone (non-acidic)

Question 33

How is Sulindac converted to its active metabolite?

Answer 33

the sulfoxide group is reduced to the active sulfide intermediate in the circulatory system

Question 34

How is Nabumetone converted to its active metabolite?

Answer 34

Metabolized rapidly to 6-methoxynaphthalene-acetic acid (6-MNA), which is an effective inhibitor of COX

Question 35

Explain the structural basis of selective COX-2 inhibitors

Answer 35

- Selective COX-2 inhibitors exploit the larger NSAID binding site in COX-2 (valine) with larger and relatively rigid substituents - Prevented from binding to COX-1 because of the smaller isoleucine binding site

Question 36

Describe the mechanism of elevated blood pressure caused by selective COX-2 inhibitors

Answer 36

- Constitutive expression of COX-2 in endothelium is critical for production of PGI-2 (prostacyclin) - High PGI-2 production → dilation of blood vessels & inhibited aggregation of platelets

Question 37

Describe the mechanism of accelerated atherogenesis caused by selective COX-2 inhibitors

Answer 37

- Selective COX-2 inhibitors do not affect the production of TXA-2 by COX-1; heightened thrombotic response on the rupture of atherosclerotic plaque - Lower levers of TXA-2 → no constriction to combat dilation, no aggregation being promoted

Question 38

List the side effects of selective COX-2 inhibitors

Answer 38

elevated blood pressure accelerated atherogenesis

Question 39

List examples salicylates

Answer 39

Salicylic acid Aspirin Salsalate (Disalcid) Diflunisal (Dolobid)

Question 40

List examples of arylacetic acids

Answer 40

Indomethacin (Indocin, Tivorbex) Sulindac (Clinoril) Etodolac (Lodine) Diclofenac (Cataflam, Voltaren)

Question 41

List examples of non-carboxylates

Answer 41

Nabumetone (Relafen) Meloxicam (Mobic, Vivlodex)

Question 42

List examples of COX-2 selective inhibitors

Answer 42

Celecoxib (Celebrex)

Question 43

List examples of eicosanoid drugs

Answer 43

Alprostadil (Edex) Misoprostol (Cytotec) Latanoprost (Xalatan, Monopost) Prostacyclin (Epoprostenol)