NSAIDS

Question 1

NSAIDs

Answer 1

nonsteroidal anti-inflammatory drugs

Question 2

used of NSAIDs

Answer 2

analgesic - pain relief
anti-inflammatory - reduce swelling
antipyretic - reduce fever

Question 3

NSAIDs mechanism of action

Answer 3

inhibition of cyclooxygenases (COX) - preventing the synthesis of prostaglandins from arachidonic acid

intended target: COX-2 - cytokine regulated enzyme => formation of prostaglandins that mediate inflammatory response, enhance pain perception, increase body temp

other target: COX-1 = for protection of the gastric mucosa, platelet, and kidney function (produced all times - constant levels)

Question 4

NSAID drug 1

Answer 4

ACETYLSALICYLATE (aspirin) - covalently modifies both COX-1 + COX-2 = permenantly inactivating these enzymes

also used to prevent atherosclerotic plaques/blood clots => heart attack/stroke

Question 5

why is aspirin more effective than salicylic acid

Answer 5

acetyl group = reduces irritability/acidity of stomach

= covalently bonds to COX enzymes

Question 6

side effects of aspirin

Answer 6

1. stomach irritation
2. ulceration of stomach lining
3. internal bleeding (if platelet disorder/taking anticoagulants)
4. kidney failure
5. tinnitus (ringing in ear)
6. drug allergy
7. Reye syndrome
8. overdose: respiratory alkalosis with respiratory depression/ rebound acidosis

Question 7

NSAID drug 2

Answer 7

ACETAMINOPHEN
analgesic, antipyretic // weak/no anti-inflammatory activity
no effects on stomach/platelets at therapeutic dose
overdose = liver toxicity
do not take with alcohol

Question 8

is COX-3 the target of Acetaminophen

Answer 8

• splice variant of COX-1 gene = retention of intron 1
• expression of canine COX-3 in insects => protein that catalyzes PG12 formation - inhibited by acetaminophen

positive results for cox 3 protein in dogs
retention of intron 1 = frameshift - truncated protein

Question 9

is COX-2 the primary target

Answer 9

measured the levels of specific markers of cox-1/2 based metabolism of arachnoid acid in human blood samples following acetaminophen treatment

cox-2 inhibition has an IC50 value 4x smaller than cox-1
maximal inhibition of cox-2 greater than cox-1
-antiinflammatory - target outside CNS
headache/fever - target enzymes inside CNS

Question 10

phenyl propionic acid derivatives

Answer 10

IBUPROFEN, naproxin
analgesic, antipyretic, anti-inflammatory actions of aspirin but fewer side effects
less COX-1 selective than aspirin
used to treat symptoms of rheumatoid arthritis/ chronic inflammatory diseases

Question 11

why is ibuprofen better inflammatory than aspirin

Answer 11

greater effect on COX-2

Question 12

COX-2 inhibitors

Answer 12

CELECOXIB
non-covalent binding to COX-2
analgesic, antipyretic, anti-inflammatory effects
no effects on platelets / fewer GI side effects
most effective treatment for rheumatoid arthritis /osteoarthritis

Question 13

difference between cox-1/cox-2 binding pockets

Answer 13

cox-2 = bulky group attached - enable binding to side pocket

Question 14

comparative key residue in cox-1/cox-2

Answer 14

cox-1 - longer occupies binding pocket

cox-2 single a.a residue - short side chain - space for side pocket

Question 15

what do most non-selective cox inhibitors share

Answer 15

a linear arrangement of functional groups

Question 16

structure of selective cox-2 inhibitors

Answer 16

shaped like an arrowhead
3 rings, sulfate group coming off ring
side chain = selectivity of cox-2 drug

Question 17

why were some cox-2 selective agents removed from shelves

Answer 17

increase in heart attacks /strokes in clinical trials
increased risk of cardiovascular effects
= cox-2 vital for cardiovascular health

Question 18

NSAIDs and Cancer

Answer 18

study showed a reduction in colon cancer with daily intake of aspirin (low dose)
anticancer ability = both COX-dependent/independent effects
mechanism: decreased cell proliferation, increased apoptosis, inhibition of angiogenesis (development of new blood vessels)