Non-steroidal Anti-

Inflammatory Drugs

And Their Effect on Renal Function
Adverse effect of NSAIDs
1
2
P harmological actions of NSAIDs
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 bodys 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
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
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
The Kidney
Adverse effects
Nephrotoxic
Bleeding problems
Increase blood pressure

FDA fact:
>70,000 hospitalizations per year and 10,000-20,000
deaths per year can be associated with NSAID use
Increased GI bleed
SSRIs
Salicylates
Anticoagulants
H2 blockers
Bisphosphonates?

Increased risk of nephrotoxicity
Cyclosporine
Methotrexate
Triamterene
Tacrolimus
Aminoglycosides


Effect of Prostaglandins on Renal Function
Vasoconstriction via their effect on the anti-
diuretic hormone (ADH). Decreased
reabsoprtion of chloride in the proximal
tubule. The proximal tubule re-absorbs
about 60% of water and solutes.

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.