27 - NSAID Flashcards
What is the definition of pain
An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage
Allodynia
Pain due to a stimulus which does not normally provoke pain
Hyperalgesia
An increased response to a stimulus which is normally painful
Acute pain
Injury due to tissue damage which will heal soon ( can be post-operative)
Types of chronic pain
Nociceptive
Neuropathic
Visceral
Mixed
Examples of nociceptive pain
Osteoarthritis and rheumatoid
Symptoms of nociceptive pain
Aching, constant
may be dull or sharp
worse with movement
well localised
What is Hilton’s law
Nerves that supply a joint capsule also supply the muscles that move that joint and the skin over the joint
Total value of NSAIDs and COX2s
35% of the market
WHO analgesic ladder
1) Non opiods, NSAIDs
2) Weak opioids
3) Strong opioids, methadone
4) Nerve block, epidural, PCA pump
What is the MoA for NSAIDs
Inhibit COX1 + COX2
What percentage of COX-2 has to be inhibited to be effective as an anti-inflammatory
80%
Aspirin
Cox-1 and COX-2 inhibitor
Anlagesic, antipyretic, anti-inflammatory
Ibuprofen, diclofenac, ketoprofen
COX 1 and COX2 inhibition + additional mechanisms
Analgesic and anti-inflammatory
Selective COX-2 inhibitors
Rofecoxib
Celecoxib
Meloxicam
structure of COX1 and 2
Hydrophobic channel with an active site
NSAIDs mainly for inflammation
Aceclofenac, etoricoxib, fenbufen, tiaprofenic acid
NSAIDs for inflammation and pain
Acematcin, celecoxib, diclofenac, ibuprofen, indomethacin, naproxen and piroxicam
NSAIDs mainly for pain
Paracoxib
Mode of action of NSAIDs
Inhibit the production of prostaglandins
How does COX help in the production of prostaglandins
Arachidonic acid is inserted into the hydrophobic channels in COX1 and COX2
interacts with molecular oxygen to produce pg
What is produced from Arachidonic acid
Prostacyclins
Prostaglandins
Thromboxanes
Function of prostacyclines (PGI)
Vasodilation, Hyperalgesia, Stops Platelet Aggregation
Function of thromboxanes
Thrombotic, vasoconstrictor
PG F2
Bronchoconstrictor, myometrial constriction
PG D2
Inhibits platelet aggregation, vasodilator
PG E2
Vasodilator, Hyperalgesic
Difference between COX2 and COX1
the hydrophobic channel of cox1 is narrower and cox2 is wider and less rigid (has higher intrinsic activity)
Where is COX-1 found and why
Brain, Lungs, Kidney, Stomach, Uterus, Skin
As prostaglandins are needed for normal function
Prostaglandin receptor
G-protein coupled receptor
COX2
Inducible by pro-inflammatory cytokines
COX-2 in joints
Causes vasodilation + symptoms
nitric oxide synthase can induce
What type of COX is in the stomach
COX1 isoform
Where are the COX1s in the stomach
In crypts
What is the function of COX1 in the stomach
To decrease the gastric acid secretion and increase the mucus secretion to protect the gut
Where is COX2 in the stomach
Superficial mucosa (small amouts)
What condition can NSAIDs lead to in the stomach
Ulceration as blocks the mucus and increases acid
Aspirin in the CVS system
Gives long lasting protection of platelet aggregation by stopping thromboxane (which aggregates platelets)
Which COX enzymes are present in the nervous system
Both however not in the same location
Function of PG in the kidney
Vasodilate the afferent arteriole
Where is COX2 present in the kidney
Macula densa
What do NSAIDs do in the kidney
Vasoconstrict the afferent areriole and decrease GFR
NSAIDs with Rapid competitive reversible binding of COX1/2
Ibuprofen
Piroxicam
NSAIDs which Rapid lower affinity reversible binding, followed by time-dependent, high affinity slowly reversible binding of COX1/2 (gives immediate effect, comes out then goes back, slow to break down )
Diclofenac
Idomethacin
NSAIDs which rapid, reversible binding followed by covalent modification of COX1 and or COX2 non-competitive irreversible
Aspirin
Adverse effect of Rofecoxib
CVS events such as strokes
