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.