Non-steroidal AntiInflammatory Drugs
And Their Effect on Renal Function
1
Definition of the drugs & their categories
The inflammatory response & inhibition
3
Renal effects of inhibition
2
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 nonsteroidal 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-1
organ pain, platelet
constitutively
function, stomach
throughout the body
protection
COX-2
Inducible: inflammation, NSAIDs, COX 2
Inducible and
pain, fever
inhibitors including
constitutively in brain, Constitutive: synaptic celecoxib
kidney
plasticity
(Celobrex )
COX-3
Constitutively, high in pain pathways, not
acetaminophen
inflammation pathways some NSAIDs
brain, heart
NSAIDs including
aspirin
Arachidonic Acid
http://en.wikipedia.org/wiki/Image:AAnumbering.png
Prostaglandin
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:Valdecoxib.png
http://en.wikipedia.org/wiki
/Image:Rofecoxib.png
http://en.wikipedia.org/wiki
/Image:Celecoxib.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 reabsorbs about 60% of water and solutes.
• Vasoconstriction via their effect on the antidiuretic 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.