NSAIDs Flashcards
What are the three major uses of NSAIDs?
Anti-pyretic (reduce fever)
Anti-inflammatory
Analgesic (mild/moderate pain relief)
Broadly speaking, how do NSAIDs act?
They inhibit the production of prostanoids via inhibition COX enzymes
What are the main prostanoids? Where are they found?
Prostaglandins (D2, E2 and F2) Prostacyclin (PGI2) Thromboxane A2
Prostanoids are ubiquitous compounds, found in most tissues. They cannot be stored, but are released immediately they have been synthesised.
1) Where does arachidonic acid come from? 2) What does COX convert arachidonic acid to? Describe this reaction.
3) How are the prostanoids subsequently formed?
1) Arachidonic acid is freed from a phospholipid molecule by the enzyme phospholipase A2.
2) PGH2
1. Oxygenation reaction converts arachidonic acid to PGG2.
2. Peroxidation reaction, catalysed by a different part of the enzyme, converts PGG2 to PGH2.
3) PGH2 is then converted by specific synthases (named after the prostanoid) to:
- Thromboxane A2
- Prostacyclin (PGI2)
- Prostaglandin D2, E2, F2
Describe the difference between COX-1 and COX-2 iso-forms
COX-1 is a constitutively expressed enzyme with a “house-keeping” role in regulating many normal physiological processes
COX-2 is an enzyme facultatively expressed in inflammation (called upon by tissue injury and other stimuli such as lipopolysaccharide (LPS), interleukin-1, and tumor necrosis factor alpha (TNFα))
How are prostanoid receptors named?
Prostanoid receptors aren’t very specific - they are named based on which prostanoid they have the highest affinity for (e.g. DP1 has the highest affinity for PGD2)
List all the prostanoid receptors.
DP1, DP2 EP1, EP2, EP3, EP4 FP IP1, IP2 TP
What type of receptor are all the prostanoid receptors?
G protein coupled receptors (though not all their actions are G protein mediated)
Explain why the EP receptor system is complex.
- There are four different EP receptors
- cAMP-dependent and independent downstream mechanisms
State some unwanted actions of PGE2.
- Increased pain perception (prostaglandins sensitise nociceptors)
- Increased body temperature
- Acute inflammatory response
- Immune responses
- Tumorigenesis
- Inhibition of apoptosis
How does PGE2 increase pain perception/lower the pain threshold (hyperalgesia)?
There is involvement of EP4 receptors and endocannabinoids
The mechanism is unclear
How does PGE2 affect body temperature?
PGE2 stimulates hypothalamic neurones initiating a rise in body temperature
NOTE: there is a bit of a lag between PGE2 rising and temperature rising
State some desirable actions of PGE2 and other prostanoids.
GASTROPROTECTION
Regulation of renal blood flow
Bronchodilation
Vasoregulation (dilation and constriction)
Describe the gastroprotective action of PGE2.
PGE2 downregulates stomach acid production
PGE2 stimulates mucus production
PGE2 stimulates bicarbonate production
What side-effect do NSAIDs have on the GI tract?
Increased risk of GI ulceration
What main effects does PGE2 have on the kidneys?
Increase renal blood flow
What effect do NSAIDs have on the kidneys?
Constriction of the afferent arteriole
Reduction in renal artery flow
Reduced GFR
Why should NSAIDs not be given to asthma patients?
Most prostaglandins are bronchodilators, so a reduction in prostaglandin production due to COX inhibition could exacerbate asthma
Inhibition of COX favours the production of leukotrienes, which are bronchoconstrictors (note that leukotrienes are products of the lipooxygenase pathway derived from arachidonic acid)
Prostanoids are vasoregulators, so what are the consequences of NSAIDs on the cardiovascular system?
Increased risk of MI and stroke because chronic use of NSAIDs cause:
- Small rise in blood pressure
- Sodium retention
- Vasoconstriction
- Reduced effectiveness of anti-hypertensives
What is the difference in terms of risk of side effects when using NSAIDs for analgesic use compared to anti-inflammatory use?
Analgesic use (only occasionally used) - low risk of side effects
Anti-inflammatory use (often sustained use with higher doses)
- higher risk of side effects
Name two non-selective COX inhibitors.
Ibuprofen
Indomethacin
Name a COX-2 selective inhibitor.
Celecoxib
What is the major problem with COX-2 selective NSAIDs?
They have a significantly increased risk of cardiovascular disease than conventional NSAIDs
Describe the relative GI and CVS risks of COX-1 selective and COX-2 selective NSAIDs when compared to non-selective NSAIDs.
COX-1 selective:
- Same CVS risk as non-selective NSAIDs
- Increased GI risk
COX-2 selective:
- Decreased GI risk
- Increased CVS risk
