3882 S2 04 Cryer
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Non-steroidal Anti-Inflammatory DrugsAnd Their Effect on Renal Function
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Definition of the drugs & their categories
The inflammatory response & inhibition
Renal effects of inhibition
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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).
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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.
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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.
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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.
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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.
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COX Expression Function Inhibitors
COX-1constitutively throughout the body
organ pain, platelet function, stomach
protection
NSAIDs including aspirin
COX-2Inducible and constitutively in brain, kidney
Inducible: inflammation, pain, feverConstitutive: synaptic
plasticity
NSAIDs, COX 2 inhibitors including celecoxib
(Celobrex )
COX-3Constitutively, high in
brain, heart pain pathways, not inflammation pathways
acetaminophen some NSAIDs
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Arachidonic Acid
Prostaglandin
http://en.wikipedia.org/wiki/Image:AAnumbering.png
http://en.wikipedia.org/wiki/Image:Prostaglandin_E1.svg
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The Biosynthetic Pathway
http://www.cem.msu.edu/~reusch/VirtualText/Images3/eicosoid.gif
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Kiefer et al. Nature 405, 97-101 (2000)
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Inhibition of COX by Aspirin
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Kiefer et al. Nature 405, 97-101 (2000)
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Non- Selective COX Inhibitors
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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
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Binding of COX-2 Inhibitor
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The Kidney
http://www.vet.ed.ac.uk/News_items/LionKid.jpg
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The Nephron
http://mcdb.colorado.edu/courses/3280/images/kidney/nephron.gif
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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).
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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.
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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.
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