1. Non-steroidal Anti-
Inflammatory Drugs
And Their Effect on Renal Function

2. 1 Definition of the drugs & their categories
The inflammatory response & inhibition 2
3 Renal effects of inhibition

3. Nonsteroidal Anti-Inflammatory Drug
• A therapeutic agent which relieves pain and
fever by inhibiting the inflammatory
response.
• These drugs are available over the counter
and by prescription.
• Some common examples include aspirin,
ibuprofen, Celebrex, and less commonly
acetaminophen (Tylenol).

4. Categories of NSAIDs
• There are two major categories for non-
steroidal anti-inflammatory drugs
• The first is non-selective anti-inflammatory
drugs.
• The second is selective anti-inflammatory
drugs, COX-2 inhibitors.

5. The Inflammatory Response
• The body’s response to a stimuli which
causes pain and/or tissue damage.
• Physiologically capillaries become “leaky”
through vasodilation.
• The response is initiated by the chemical
messengers prostaglandins.

6. Prostaglandins
• Prostaglandins were isolated from human
semen in 1936 by Ulf von Euler. He named
them Prostaglandins because he believed
they came from the prostate gland.
• The Swedish scientist received the Nobel
Prize in medicine in 1970 for this work.
• Since his work in this area it has been
determined that they exist and are
synthesized in almost every cell of the body.
• They are synthesized in the same cell on
which they act.

7. Biosynthesis of Prostaglandins
• The goal is to inhibit the biosynthesis of
prostaglandins in order to relieve the
symptoms caused by the inflammatory
response.
• Prostaglandins are synthesized from
arachidonic acid in a pathway mediated by
the Cyclooxygenase enzymes.

8. COX Expression Function Inhibitors
organ pain, platelet
constitutively function, stomach NSAIDs including
COX-1 throughout the body aspirin
protection
Inducible: inflammation, NSAIDs, COX 2
Inducible and pain, fever inhibitors including
COX-2 constitutively in brain, Constitutive: synaptic celecoxib
kidney
plasticity (Celobrex )
Constitutively, high in pain pathways, not acetaminophen
COX-3
brain, heart inflammation pathways some NSAIDs

9. Arachidonic Acid
http://en.wikipedia.org/wiki/Image:AAnumbering.png
Prostaglandin
http://en.wikipedia.org/wiki/Image:Prostaglandin_E1.svg

10. The Biosynthetic Pathway
http://www.cem.msu.edu/~reusch/VirtualText/Images3/eicosoid.gif

12. Kiefer et al. Nature 405, 97-101 (2000)

14. Inhibition of COX by Aspirin

15. Kiefer et al. Nature 405, 97-101 (2000)

16. Non- Selective COX Inhibitors

17. Selective COX-2 Inhibitors
http://en.wikipedia.org/wiki http://en.wikipedia.org/wiki http://en.wikipedia.org/wiki
/Image:Valdecoxib.png /Image:Rofecoxib.png /Image:Celecoxib.png

18. Binding of COX-2 Inhibitor

19. The Kidney
http://www.vet.ed.ac.uk/News_items/LionKid.jp
g

20. The Nephron
http://mcdb.colorado.edu/courses/3280/images/kidney/nephron.gif

21. Effect of Prostaglandins on Renal Function
• Decreased reabsoprtion of chloride in the
proximal tubule. The proximal tubule re-
absorbs about 60% of water and solutes.
• Vasoconstriction via their effect on the anti-
diuretic hormone (ADH).

22. Inhibition of Prostaglandin Synthesis
• When COX-2 inhibitors are administered
absorption is altered in the proximal tubule.
• Also, because they enhance the effect of
ADH, vasoconstriction occurs reducing the
glomelular filtration rate (GFR).
• Any abrupt reduction in GFR can result in
acute renal failure.

23. No Need for Alarm
• For a normal healthy person, NSAIDs are
not going to cause renal failure. The kidney
adapts very well to changes in GFR in
healthy patients.
• NSAIDs become a problem when they are
used for very long terms, and in patients who
already have a decreased GFR caused by
high blood pressure, congestive heart failure,
or chronic renal disease.