3882 S2 04 Cryer


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3882 S2 04 Cryer

  1. 1. Non-steroidal Anti- Inflammatory Drugs And Their Effect on Renal Function
  2. 2. 1 Definition of the drugs & their categories The inflammatory response & inhibition 2 3 Renal effects of inhibition
  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. 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. 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. 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. 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. 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. 9. Arachidonic Acid http://en.wikipedia.org/wiki/Image:AAnumbering.png Prostaglandin http://en.wikipedia.org/wiki/Image:Prostaglandin_E1.svg
  10. 10. The Biosynthetic Pathway http://www.cem.msu.edu/~reusch/VirtualText/Images3/eicosoid.gif
  11. 11. Kiefer et al. Nature 405, 97-101 (2000)
  12. 12. Inhibition of COX by Aspirin
  13. 13. Kiefer et al. Nature 405, 97-101 (2000)
  14. 14. Non- Selective COX Inhibitors
  15. 15. 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
  16. 16. Binding of COX-2 Inhibitor
  17. 17. The Kidney http://www.vet.ed.ac.uk/News_items/LionKid.jp g
  18. 18. The Nephron http://mcdb.colorado.edu/courses/3280/images/kidney/nephron.gif
  19. 19. 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).
  20. 20. 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.
  21. 21. 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.