NSAIDs - Mechanism of Action, analgesic, antipyresis, anti-inflammatory effects

Mechanism of Acion 

The non-steroidal anti-inflammatory drugs act primarily by inhibiting the synthesis of prostaglandins, the mediators involved in nociception and pathogenesis of inflammation and fever.  These drugs block the cyclooxygenase (COX) enzyme either reversibly (e.g. most NSAIDs) or irreversibly (e.g. aspirin) causing inhibition of synthesis of prostaglandins (PGs), prostacyclin (PGI₂) and thromboxane A₂ (TXA₂). This mechanism of action was elucidated by John Vane (1927-2004), who received a Nobel Price for this work in 1982. Cyclooxygenase enzyme occurred in two isozymes: cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). The COX-1 is a constitutive enzyme and is considered to be necessary for normal homeostasis, while COX-2 is mainly inducible (induced by cytokines such as IL-1 in inflammation) and is considered to be associated with inflammation and pain. Most of NSAIDs inhibit both COX-1 and  COX-2 non-selectively, although ratio for the inhibition of COX-1 : COX-2 varies widely being high for aspirin, phenylbutazone and piroxicam, and low for naproxen, carpofen and meloxicam. Some newer NSAIDs (e.g. celecoxib, rofecoxib and firocoxib) selectively inhibit COX-2. The relatively bulky structure of COX-2 inhibitors prevents COX-1 inhibition by steric hindrance. Most of the toxic effects (e.g. GI irritation, retinotoxicity and interference with clotting mechanism) of non-selective inhibitors of COX-1 and COX-2 are due to inhibition of COX-1, while desirable anti-inflammatory and analgesic actions are attributable to blockade of COX-2 also has some constitutive functions associated with renal, nerve, brain, ovaries, uterus and bones; therefore the associated side effects with these system may not be completely eliminated with selective COX-2 inhibitors.

Other proposed mechanisms of action for some NSAIDs include inhibition of neutrophils function, blockade of oxygen radical production, stabilization of lysosomal enzymes, antagonism of bradykinin release, modulation of nitric oxide synthesis, alteration of signal transduction mechanisms, or inhibition of metalloproteinase activity. Some NSAIDs (e.g. aspirin) are reported to influence cytokines production. Non-steriodal anti-inflammatory drugs (except licofelone), however, do not inhibit lipoxgenase production and hence do not suppress leukotrienes formation; rather there may be more formation of leukotrienes due to more availability of arachidonic acid substrate.

Analgesia

Non-steroidal anti-inflammatory drugs produce analgesic effect mainly by inhibiting production of prostaglandins and by decreasing sensitisation of pain receptors to noxious stimuli. Prostaglandins (mainly PGE₂ and PGI₂ ) sensitize the nociceptive  afferent nerve terminals to mediators like bradykinin, cytokines (e.g. TNF-α, IL-1 and IL-8)  and some other algesic agents, so that even a small concentrationof algesic agent produces intense pain. The capacity of prostaglandins to sensitize pain receptors to mechanical stimuli appears to result from lowering  of the threshold of the polymodal nociceptors of C-fibers. Non-steroidal anti-inflammatory drugs are, therefore, mainly effective against those types of pain in which prostaglandins act to sensitize nociceptors, namely pain associated with inflammation or tissue damage. NSAIDs do not affect the hyperalgesic or the pain caused by direct action of prostaglandins. Some agents (e.g. aspirin) may also depress pain stimuli at subcortical site (thalamus and hypothalamus).

Antipyresis

Normal body temperature is regulated by a centre in the hypothalamus, which ensures a balance between the heat loss and heat production. During infection ( also tissue damage, inflammation or other disease states), there is enhanced generation of cytokines like interleukins (e.g. IL-1β and IL-6), interferons and tumour necrosis factor (TNF-α) which include PGs production, especially PGE₂ , in and near hypothalamic area. The PGE₂ via increase in cyclic AMP triggers the hypothalamus to elevate the set point at which body temperature is regulated resulting in fever. Cytokines either directly or indirectly through induction of PGs (mostly) stimulate also the vasomotor centre in the CNS resulting in sympathetic nerve stimulation, peripheral vasoconstriction, decrease in heat dissipation or fever. Non-steroidal anti-inflammatory drugs apparently reset the ‘set point or thermostat’ and also increase heat loss through peripheral vasodilatation by inhibiting synthesis of prostaglandins. Non-steroidal anti-inflammatory drugs do not influence body temperature when it is elevated by factor such as exercise or rise in ambient temperature. The NSAIDs reduce body temperature in fever, but do not cause hypothermia in normothermic individuals.

Anti-inflammatory effect

Inflammation is a complex process that occurs due to participation of a large number of vasoactive, chemotactic and proliferative factors at different stages. Prostaglandins, leukotrienes, platelet activating factor, cytokines and other mediators are released by a host of mechanical, thermal, chemical, bacterial and other insults which contribute to the genesis of inflammation. Although PGs do not appear to have direct effects on vascular permeability and inflammation, PGE₂ and PGI₂ markedly enhance oedema formation and leucocyte infiltration