3882 S2 04 Cryer
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Transcript of 3882 S2 04 Cryer
Non-steroidal Anti-Inflammatory DrugsAnd Their Effect on Renal Function
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).
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.
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.
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.
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.
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
Arachidonic Acid
Prostaglandin
http://en.wikipedia.org/wiki/Image:AAnumbering.png
http://en.wikipedia.org/wiki/Image:Prostaglandin_E1.svg
The Biosynthetic Pathway
http://www.cem.msu.edu/~reusch/VirtualText/Images3/eicosoid.gif
Kiefer et al. Nature 405, 97-101 (2000)
Inhibition of COX by Aspirin
Kiefer et al. Nature 405, 97-101 (2000)
Non- Selective COX Inhibitors
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
Binding of COX-2 Inhibitor
The Kidney
http://www.vet.ed.ac.uk/News_items/LionKid.jpg
The Nephron
http://mcdb.colorado.edu/courses/3280/images/kidney/nephron.gif
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).
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.
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.