NSAIDs in RA treatment Flashcards
What is the only irreversible inhibitor or COX?
Asprin is the only irreversible COX inhibitor, all other NSAIDs are reveresible
Which prostaglandin is the most important in inflammation?
PGE2
How does PGE2 cause pain?
It acts on neuron nociceptive receptors that trigger an Action Potential to tell us that tissue damage has happened in a certain location.
Compare the frequency of expression of COX1 and COX2.
COX1 is constitutively expressed while COX2 is expressed on induction
What protective roles does PGE2 play in the stomach. What is the result of blocking these effects via NSAIDs?
Protective roles of PGE2 include:
• Increased: mucus secretion, cell regeneration, Bicarbonate and blood flow with..
•Decreased:H+ secretion
Failure to perform these tasks results in Gastritis and Gastric Ulcers
**Note that NSAIDs have some direct effects on stomach mucosa too (see below)
What are some risk factors for experiencing the adverse GI effects of NSAIDs?
• which drugs have to lowest risk of causing adverse GI effects?
People who are old or have a history of GI ulcers, or infection as well as comorbities (CHF, HTN, Diabetes) and those taking concurrent medications. Also heavy EtOH use and heavy smoking predispose you to GI issues while taking NSAIDs.
Drugs LEAST likely to causes these problems are COX-2 specfic and include Celecoxib and Diclofenac. Drugs MOST likely to cause issues are Naproxen (#1) and Ibuprofen.
What methods have been implemented to reduce the GI toxicity of NSAIDs?
• what might be the problem with some of these methods?
Enteric coatings have been implemented. Taking NSAIDs with food hasn’t been proven and actually may attenuate the effects of the drug leading to the patient taking additional doses.
Perhaps the MOST IMPORTANT thing you can do is take PPIs or H2 inhibitors with NSAIDs (even COX-2 specific drugs).
The problem with taking PPIs is that reduction in stomach acidity may affect the absorption of some NSAIDs.
What is the major problem with taking COX-2 specific NSAIDs (Celecoxib) if you have a history of blood clots?
• what biochemisty underlies this phenomenon?
COX-2 inhibitors cause increased risk of thrombosis. This is because COX-2 which produces PGI2 (a vasodilating, anti-thrombotic prostaglandin) gets inhibited while COX-1 which produces TXA2 is left alone. With a screwed up PGI2-TXA2 balanace patients are left in a prothrombotic state.
What is the only NSAID that can be taken in high dose without increasing the risk of thrombotic events?
NAPROXEN
**Even ibuprofen has been implicated in CV events at high dose**
What risk do you run giving an additional NSAID to a patient taking 81mg of low asprin daily to reduce the risk of having another MI?
Other NSAIDs may inhibit the ability of asprin to IRREVERSIBLY inhibit COX-1 on platelets and thus there is only reversible inhibition with continued production of TXA2 when the NSAID is lost in the bloodstream.
Which NSAID is most likely to cause liver damage?
Sulindac
Why are COX-2 selective drugs not known to reduce adverse effects on the kidney compared to other NSAIDs?
Celecoxib and other COX-2 specific drugs reduce COX blocking side effects because COX-2 is inducible and not constantly expressed throughout the body as COX-1 is. COX-2 is typically upregulated in a sites of inflammation causing increased vasodilation and reduces downsteam coagulation via PGI2 and tells you that the tissue is injured via PGE2.
COX-2 while inducible everywhere else is CONSTANTLY EXPRESSED (in the macula densa to act on the afferent arterioles) IN THE KIDNEY TO REGULATE VASDILATION OF THE AFFERENT ARTERIOLES.
What 2 negative effects most often occur as a result of NSAID use in the kidney?
• who are we most likely to see these negative effects in?
COX-2 in the kidney gets inhibited resulting in reduction of PGIs and E2 and a loss of vasodilation in the Afferent arteriole. This results in a 1reduced GFR and may preciptate 2Acute Renal Failure due to a lack of perfusion through the peritubular capillaries.
NSAID adverse effects are most likely to be seen in Old people and people with comorbidities such as Glomerular Disease, CHF pts, Cirrhosis, Volume depleted people.
What 2 important drugs do NSAIDs prevent the clearance of?
Lithium and Methotrexate
What things might you see in urinalysis that indicate adverse effects as a result of NSAID use?
• WHY might you see these changes?
Hematuria, Pyuria, WHITE CELL CASTS, proteinuria, and acute renal insufficiency.
These abnormalities may be caused by:
• Interstitial Nephritis - White Cell Casts
• Membranous Nephropathy - Proteinuria (subendothelial spikes)
• Minimal Change Disease - proteinuria (podocyte effacement)
