NSAIDs

The term "NSAIDs" stands for non-steroidal anti-inflammatory drugs. They were originially obtained from plant extracts such as willow bark, which contain agents known as salicylates. Aspirin was synthesised for the first time in 1893, and in 1972 the mode of NSAID action was discovered to be associated with cyclo-oxygenase inhibition.

Mechanism of Action

NSAIDs are defined as "agents which inhibit the formation of eicosanoids from arachidonic acid". Prostaglandins (PGs), thromboxanes (TXs) and leukotrienes (LTs) are all eicosanoids which have an inflammatory-mediating action.

Chemical or physical injury to cells causes induction of the enzyme phospholipase-A2 (PLA2), which converts phospholipids to arachidonate. This newly-formed arachidonic acid is converted by the action of cyclo-oxgygenase (COX) enzymes to cyclic endoperoxidases, which can form inflammatory mediators including PGI2, PGD2, PGE2 and TXA2. Arachidonte may also be converted to 5-HPETE to eventually form leukotrienes, and some newer NSAIDs target this branch of the pathway.

NSAIDs interfere with the formation of inflammatory mediators by inhibiting the action of the enzyme cyclo-oxygenase. Two forms of the enzyme exist: COX-1, which is constitutively expressed, and COX-2, which is inducible and produced by inflammatory cells. To minimise the potential for side-effects of using NSAIDs for anti-inflammatory purposes it would be ideal to target COX-2 only, leaving the "housekeeping" functions of COX-1 intact. However, most NSAIDs are non-selective COX inhibitors.

Actions

Acting centrally, NSAIDs provide analgesia. The degree of analgesia provided is dependent on the type and cause of the pain in question. For example, NSAIDs are very effective at relieving post-operative pain. They also work well in instances of hyperalgesia, where inflammation causes sensitisation of pain receptors. This is because NSAIDs prevent the formation of pain-producing prostaglandins that would otherwise be formed under the influence of pro-inflammatory cytokines such as IL-1 and TNF-a.

NSAIDs also have anti-pyretic properties when acting centrally. Normally in pyrexia, IL-1 induced prostaglandin release causes the hypothalamus to raise the temperature "set-point". Because NSAIDs reduce prostaglandin production, this process is disrupted.

Non-steroidal anti-inflammatories also act peripherally. As well as the anti-inflammatory and analgesic actions you might expect, NSAIDs have anti-endotoxic and anti-thrombotic funtions. The anti-endotoxic action works by the drug preventing the release of vasoactive mediators from leucocytes and vascular endothelium following endotoxic insult. Finally, NSAIDs have effects on cartilage which may be both beneficial and adverse.