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

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

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

9. Arachidonic Acid Prostaglandin http://en.wikipedia.org/wiki/Image:AAnumbering.png 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 /Image:Celecoxib.png http://en.wikipedia.org/wiki /Image:Rofecoxib.png http://en.wikipedia.org/wiki /Image:Valdecoxib.png

18. Binding of COX-2 Inhibitor

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

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.