2.4 Anti-Inflammatory Drugs Flashcards
What are NSAIDs?
Non-Steroidal Anti-Inflammatory Drugs
NSAIDs have several important effects as a result of inhibiting prostanoid production via inhibiting cyclo-oxygenase (COX). What are these effects?
- Analgesic (pain relief)
- Anti-inflammatory
- Antipyretic (decrease body temp)
- Anti-platelet (reduce/prevent coagulation)
Prostaglandin (PG) E2, prostacyclin (PGI2), and thromboxane A2 are all results of biosynthesis via the arachidonic acid cascade. How do NSAIDs impact this process?
Arachidonic acid cascade = enzymatic conversion into biologically active metabolites via cyclo-oxygenase (COX)
NSAIDS inhibit COX
Without COX, arachidonic acid is unable to continue conversion / biosynthesis
Redness, heat, swelling, and pain are core components of an inflamamtory response. How are prostaglandins involved with these features?
PGE2 + PGI2 cause vasodilation (redness + heat)
PGE2 + PGI2 potentiate effects of histamine + bradykinin = causes capillary leakage and sensitises afferent C fibres (swelling + pain)
Anti-inflammatory + analgesic effects of NSAIDs are due to COX inhibition and consequent reduction in prostaglandin formation. How does this limit the anti-inflammatory actions of NSAIDs?
NSAIDs do NOT effect underlying inflammatory disease
No impact on cytokine/chemokine release, leukocyte migration, and oxygen free radical formation = important part of damage in CHRONIC inflammatory conditions
COX inhibition by NSAIDs can have therapeutic symptomatic relief from fever, pain, and swelling in chronic joint disease and other situations, but can have negative side effects depending on the COX isoform targeted. What are the 2 types of COX isoform?
COX-1 = ubiquitous distribution, cytoprotective effect on gut mucosa reducing acid secretion + promoting mucus production
COX-2 = not normally present, induced by inflamamtory mediators (important target)
What are 6 (of over 50) examples of NSAIDs and what are their respective COX selectivity + effects?
- Aspirin = COX-1, anti-platelet effects, irreversible, GI effects
- Ibuprofen = weak COX-1, suitable for children
- Indomethacin = weak COX-1, suitable for moderate-severe
- Meloxicam = moderate COX-2, few GI effects
- Diclofenac = moderate COX-2, moderate potency
- Celecoxib = COX-2, least GI effects
COX-1 and COX-2 binding sites both contain a hydrophobic tunnel which NSAIDs use. What is the main difference between these binding sites?
COX-1 = small binding site
COX-2 = side pocket which accomodate bulky groups such as coxibs
NSAIDs mechanism of action is the inhibition of prostaglandins, explaining the majority of therapeutic actions as well as their side effects. How do NSAIDs induce side effects?
COX-2 inhibition = only wanted anti-inflammatory + analgesic effects
COX-1 + COX-2 inhibition = unwanted GI effects + cardiovascular effects as well
GI toxicity is a common side effect of NSAIDs. Why?
Prostaglandins protect gastric mucosa from stomach acid via increased blood flow, increased mucosa production, increased bicarbonate secretion, and decreasing gastric acid secretion
By inhibiting PGs, these effects are also inhibited
GI toxicity is a common side effect of NSAIDs. Why?
Prostaglandins protect gastric mucosa from stomach acid via increased blood flow, increased mucosa production, increased bicarbonate secretion, and decreasing gastric acid secretion
By inhibiting PGs, these effects are also inhibited
GI toxicity is a common side effect of NSAIDs. Why?
Prostaglandins protect gastric mucosa from stomach acid via increased blood flow, increased mucosa production, increased bicarbonate secretion, and decreasing gastric acid secretion
By inhibiting PGs, these effects are also inhibited
GI toxicity is a common side effect of NSAIDs. Why?
Prostaglandins protect gastric mucosa from stomach acid via increased blood flow, increased mucosa production, increased bicarbonate secretion, and decreasing gastric acid secretion
By inhibiting PGs, these effects are also inhibited
Coxcibs are a common alternative to traditional NSAIDs for aptients with high risk of serious GI side effects. However, they have a different associated aide effect, what is it and why ?
Cardiovascular risk
COX-2 suppress PGI2 in vascular endothelium leading to hypertension + thrombosis = increased risk of MI or stroke
