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.

Pharmacokinetic Considerations

Pharmacokinetics for NSAIDs differ greatly between species, meaning that data from one species cannot be used to reliably calculate a dose for another.

Some drugs may display zero-order kinetics, i.e. the rate of metabolism of the drug is constant and does not vary with dose. This is the case for phenylbutazone in the dog and salicylate in the cat.

NSAIDs may be administered orally or parentally. As they are weak acids, NSAIDs are well absorbed from the stomach following oral administration. The presence of food may, however, interfere with this absorption. Once absorbed, NSAIDs have a small apparent volume of distribution. In actuality, the magnitude is not that small; the drugs accumulate at sites of inflammation due to plasma protein escaping through leaky blood vessels in these locations. This is a good property - the drug reaches the areas where it is needed most.

The half-life of NSAIDs is often short, and so dosing is required every 4 to 6 hours. Despite this, the duration of action is quite long: although the drug leaves the plasma rapidly it remains bound to the COX enzyme for more extended periods.

NSAIDs primarily undergo hepatic metabolism and excretion, which is slow before six weeks of age. Some metabolites such as oxyphenbutazone and salicylate are active. There is some excretion of unaltered drug in the urine, which is enhanced by an alkaline pH. This is an example of ion trapping: since NSAIDs are weak acids, there is a greater degree of ionisation in an alkaline environment, making it more difficult for the drug to cross membranes and escape back to the circulation.

Non-steroidal anti-inflammatory drugs have a high degree of plasma protein binding (approaching 99%). This means that other highly plasma protein-bound drugs with stronger binding affinities may displace NSAIDs from their binding. This would lead to an increase in circulating free drug levels and hence potential overdose. Although this is a theoretical risk, it has been demonstrated in relation to warfarin administration.

Side Effects and Contraindications

The side effects associated with the use of NSAIDs are related to theie non-specific inhibition of COX enzymes. The constitutively expressed COX-1 has many functions within the normal body, and suppression of these may lead to adverse reactions.

Gastro-intestinal prostaglandins (for example, PGI2 and PGE2) normally have a protective influence over the gastric mucosa, by inhibiting the secretion of gastric acid and promoting that of mucus. NSAID inhibition of COX-1 function leads to the reduced synthesis of these prostaglandins, causing ulceration of the gastro-intestinal tract. Lesions of the large intestine have also been demonstrated following the use of phenylbutazone in the horse. Although NSAIDs are normally absorbed in the stomach, phenylbutazone may bind to feed and become released in this more distal area of the tract resulting in ulceration.