anti-inflammatory
analgesic
anti-pyretic
Some NSAIDs may also have anti-thrombotic and anti-endotoxic effects. The proportion of each effect is probably different for each drug, but this is difficult to prove. There are major species differences.
NSAIDs are thought mainly to affect acute inflammatory processes through inhibiting the generation of thromboxane, prostacyclin, and the prostaglandins. They are not thought to dramatically affect the clinical progression of chronic inflammatory processes which are mediated by other mechanisms (many different cytokines are involved). However, chronic inflammation is often associated with intermittent episodes of acute inflammation and some degree of relief from the clinical signs associated with these episodes can be gained with the use of NSAIDs.
Chronic inflammation can sometimes lead on to cancer: NSAIDs have been shown to protect people from some of these cancers.
NSAIDs are not as effective as anti-inflammatory agents as corticosteroids. They do not delay healing in the way that steroids do.
There are a number of other possible mechanisms which may contribute:
•free radical scavenging
•upsetting oxidative phosphorylation
•disrupting G protein signaling
•inhibition of neutrophil activation
•inhibition of neutrophil adhesion
•inhibition of leukocyte recruitment
•inhibition of proteoglycan synthesis
•inhibition of phospholipase A2
•prostaglandin receptor antagonism
The way that NSAIDs produce analgesia may be different from the way they produce their anti-inflammatory effects. Both may be due to cyclo-oxygenase (COX) inhibition in various sites (althogh most NSAIDs have other effects which may also contribute to analgesia).
Steroids also reduce prostaglandin production (by acting higher up the cascade) but are not directly analgesic - they are potent anti-inflammatories and by removing inflammation they can reduce pain. NSAIDs are different in that they can produce analgesia in the absence of inflammation.
Prostaglandin receptor pharmacology is a developing field. The situation is confused at present; the receptors responsible for some effects (but not the sensitisation of neurones) have been elucidated. However, it is clear that PGD2, E2 and I2 can all sensitise peripheral neurones to the pain producing effects of bradykinin and other mediators.
Some (most??) analgesia may be produced in the CNS (probably the brain rather than the spinal cord). There is evidence that prostaglandins interact with several types of glutamate receptors to increase nociception, NSAIDs may block this.
All currently used drugs also have other effects unrelated to cyclo-oxygenase inhibition which could contribute to analgesia. Many scavenge free radicals, which will also reduce inflammation.
Bacterial endotoxins can cause the release of interleukin 1 which stimulates the generation of PGE2 in the endothelium of the hypothalamic vasculature, which is thought to be the mechanism responsible for changing the bodies normal thermostatic control setting. The use of NSAIDs will not affect normal body temperature (except in cases of toxicity) nor will they affect exertionally induced hyperthermia. They will reduce pyrexia associated with pyrogens circulating in the plasma.
NSAIDs bind to the cyclo-oxygenase enzyme in platelets inhibiting their production of thromboxane A2 (TXA2). Low doses of aspirin can preferentially inhibit the production of TXA2 relative to PGI2 by irreversibly acetylating the platelet cyclo-oxygenase and can thus be used therapeutically to decrease the likelihood of development or growth of a thrombus e.g. cats with ileal thrombosis, dogs with heartworm disease. Low dose aspirin is used therapeutically for this purpose since it covalently acetylates cyclo-oxygenase. Platelets have no nucleus and thus no protein synthesis machinery so thromboxane production is inhibited for the life of the platelet (about 7 days), whereas cyclo-oxygenase in other cell types can be replaced.
Although TXA2 generation is only part of the clotting process, the increase in blood clotting times may have implications in aspirin's use in post trauma situations where internal haemorrhage is a consideration. The other NSAIDs are less effective anti-thrombotics and do not prolong bleeding time significantly.
Bacterial endotoxins (lipopolysaccharides) are thought to produce some of their effects through prostaglandin production. There is no good evidence that NSAIDs are beneficial when given after the endotoxin, although they are often used.
