NSAIDs

Question 1

What 3 sx do NSAIDs treat?

Answer 1

Fever, pain, inflammation

Question 2

Explain ASA’s mech of action.

How do other NSAIDs act?

Answer 2

• Covalently attaches an acetyl group to the active site of COX enzymes, irreversibly inhibiting COX-1.
• Also acetylates COX-2, but the active site of COX-2 is larger/more flexible, so arachidonic acid can access active site

Other than Aspirin, all other NSAIDs competitively inhibit COX enzyme activity blocking access of arachidonic acid to the active site.

Question 3

What is the pattern of expression for COX-1 vs. COX-2?

Answer 3

• COX-1: Constitutively expressed (housekeeping)

- COX-2: inducible isoform

Question 4

In what cell types is COX-2 induced?

In what tissue types is it constitutive expressed?

Answer 4

• Induced in macrophages, fibroblasts, synoviocytes

- Constitutive in kidney, brain, and endothelium

Question 5

What is the affect of ASA on platelets? (name the molecule it acts on)
What is the appropriate dose (relative)?

Answer 5

• Anti-thrombotic (blocks pro-thrombotic thromboxane A2 AKA TXA2)
• Low dose

Question 6

Is prostatcyclin pro- or anti-thrombotic?

Why doesn’t ASA affect it?

Answer 6

• Anti-thrombotic
• COX-1 is resynthesized in the endothelium, so low-dose aspirin does not effectively inhibit the production of anti-thrombotic prostacyclins

(prostatcyclin = PGI2)

Question 7

Which NSAID has a rapid onset of action, and is ideal for fever and acute pain?

Answer 7

Ibuprofen

Question 8

Which NSAID has a rapid onset of action, a long serum half-life 14hrs, twice daily dosing?

Answer 8

Naproxen

Question 9

Which NSAID has a long serum half life- 50-60 hrs; once daily dosing?

Answer 9

Oxaproxin

Question 10

Which NSAID is a potent anti-inflammatory, > toxicity; used to close patent ductus arteriosus?

Answer 10

Indomethacin

Question 11

Which NSAID is relatively selective for COX-2 and is associated with increased risk of MI/stroke?

Answer 11

Diclofenac

Question 12

Which NSAID is mainly used as IV analgesic as a replacement for opioid analgesics?

Answer 12

Ketorolac

Question 13

What are the 2 primary adverse affects of tNSAIDs?

Answer 13

Affects of GI/stomach, as well as kidneys

Question 14

The stomach and GI disturbances caused by Aspirin and traditional NSAIDs are due to the inhibition of ________ , which is responsible for the production of PGs that act to prevent damage to gastric and intestinal epithelial cells caused by gastric acid and digestive enzymes.

Answer 14

COX-1

Question 15

COX-2 inhibitors are no more efficacious than other NSAIDs, but might be preferable in patients with
a prior history of ____________.

Answer 15

GI bleeds/ulcers

Question 16

NSAID contraindications include: (5)

include +3 that are specific contraindications for ASA

Answer 16

GI ulcers, bleeding disorders, renal disorders (elderly), pregnant, increased risk for CV dz

ASA: previous hypersensitivity to ASA, children w/febrile viral infections (can induce Reyes syndrome). ASA: gout (inhibits uric acid secretions at low doses)

Question 17

Does acetaminophen inhibit COX-1 or COX-2 in periphery? CNS?

Answer 17

• Neither in periphery

- COX-2 in CNS

Question 18

• Which of the following effects does acetaminophen have?
  a) Anti-pyrretic
  b) Anti-inflammatory
  c) Anti-platelet
  d) Analgesia

Answer 18

YES: a) Anti-pyrretic + d) Analgesia

NO: b) Anti-inflammatory + c) Anti-platelet

Question 19

Would hemophiliacs need to avoid tNSAIDs and celecoxib?

Answer 19

Yes - tNSAIDs

No - CBX (anti-platelet COX-1 spared)

Question 20

Acetaminophen OD results in the build up of the toxic metabolite ____________, which depletes hepatic ___________.

Answer 20

• NAPQI (N-acetyl benzoquinoneimine)

- Glutathione

Question 21

___________ is used as an antidote to acetaminophen OD because it replenishes endogenous glutathione levels.

Answer 21

N-acetylcysteine

Question 22

Name 3 drugs that interact w/all NSAIDs to decrease renal clearance and cause toxicity from that drug.

Answer 22

Lithium, methotrexate, aminoglycosides

Question 23

Why don’t you want to combine low dose ASA w/NSAIDs (except CBX)?

Answer 23

NSAIDs antagonize the beneficial effects of low-dose ASA.

Question 24

Combining NSAIDs w/ ______________ (like ______) increase the risk of bleeding.

Answer 24

Oral anti-coagulants (like warfarin)

Question 25

Combining NSAIDs w/ ______________ (like ______) can counteract the anti-hypertensive effects of the drug.

Answer 25

Anti-hypertensives (ACE inhibitors, beta blockers)

Question 26

What is the problem w/combining oral hypoglycemics (e.g. sulfanylureas) w/ASA?

Answer 26

Potentiate hypoglycemic effects of sulfonylureas.

Question 27

What is the problem w/diuretic agents (e.g. furosemide) w/NSAIDs?

Answer 27

NSAIDs promote Na+ and H2O retention.

Question 28

Which drugs should not be combined w/ASA, and which shouldn’t be combined w/any NSAID or NSAIDs except CBX?

Answer 28

ASA: Oral hypoglycemics (sulfonylureas)

NSAIDs: Oral anti-coagulants (e.g. warfarin), anti-hypertensives (ACE inhibitors/beta-blockers), Li, methotrexate, aminoglycosides (e.g. gentamicin), diuretic agents (e.g. furosemide).

NSAIDs except CBX: *low-dose ASA

Question 29

• Which of the following can a pt w/Reyes syndrome safely use? (which is preferable?)
  a) ASA
  b) tNSAIDs
  c) CBX
  d) Acetominophen

Answer 29

All except ASA (acetaminophen preferable)

Question 30

Regarding thromboxane A2 and PGI2, why does CBX increase CVD risk compared to low dose ASA?

Answer 30

Low dose ASA inhibits pro-thrombotic TXA2 while sparing anti-thrombotic PGI2. (=

CBX inhibits anti-thrombotic PGI2 while sparing pro-thrombotic TXA2. )=

Question 31

What is acetaminophen metabolized into?

What does this do besides working w/the drug to inhibit CNS COX-2?

Answer 31

AM404

- Also stimulates cannabinoid receptors

Question 32

What drug would be indicates for pts with a fever but also CVD?

Answer 32

Acetaminophen

Question 33

What drug would be indicates for pts with a fever but also hemophilia, w/ or w/o CVD?

Answer 33

w/ CVD: acetaminophen

w/o CVD: acetominophen (or celecoxib, but more side effects)