NSAIDs

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Introduction

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 (COX) inhibition. There are three categories of clinically used NSAIDs: non-selective COX inhibitors, preferential COX-2 inhibitors, and specific COX-2 inhibitors. In short, they decrease the production of prostaglandins and thromboxanes, which are inflammatory mediators. NSAIDs are widely used since they are multi-purpose drugs that do not induce addiction. Such uses include pain relief, fever reduction, and inflammation management.

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 their 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.

Prostaglandins have a vasodilatory action, and so local production in the kidney is important for maintaining normal renal perfusion. NSAID interference will therefore lower renal blood flow, giving rise to nephrotoxicity, and so use in renal patients must be carefully considered. Care must also be taken when administering these drugs peri-operatively.

Some NSAIDs, such as aspirin and ketoprofen, can also have negative effects on coagulation. Platelet aggregation is caused by prostaglandins and thromboxanes which are produced by platelets using a COX-1 pathway. Inhibition of this pathway can therefore cause bleeding.

Because of these issues, the use of COX-2 selective drugs is desirable. These include carprofen, meloxicam and nimesulide.

Drug Interactions

The concurrent use of two COX inhibitors will result in both additive efficacy and toxicity.

NSAIDs used with cimetidine or chloramphencicol may be subject to slower metabolism. This is because these drugs inhibit mixed function oxidases (MFOs) in the liver.

As mentioned under pharmacokinetics, displacement of NSAIDs from their plasma protein binding with other high affinity drugs such as warfarin may lead to toxicity.

Drugs in This Group

Aspirin

Aspirin is the common name for acetyl salicylic acid. This is hydrolysed to an active form, salicylate, which irreversibly binds COX by an acetylation reaction and has a high affinity for COX in platelets. Because of this affinity, the drug has an anti-thrombotic effect which is more pronounced at low doses where platelet production of TXA2 (aggregatory) is inhibited but that of PGI2 (disaggregatory) is not. At higher doses, PGI2 formation is also affected, reducing the dis-aggregatory influence it provides and therefore the anti-thrombotic effects of aspirin. Once COX is bound by salicylate, TXA2 production is inhibited for the life of that platelet, and so new platelets are required to raise body TXA2 levels again. At the low doses required for anti-thrombosis, aspirin has no analgesic or anti-inflammatory properties.

Aspirin is not used very commonly in veterinary medicine, and huge dose variations exist between species. For example, the dose for a dog is 25mg/kg/8 hours, but in the cat is 25mg/kg/day. Half-life also differs between species, being only one hour in the pony but 37.6 hours in the cat.

Oxidisation is the main method of aspirin metabolisation, but some drug is also conjugated to glucuronide. Glucuronidation cannot be performed by the cat, accounting for the long half-life in this species.

Paracetamol

Phenylbutazone

Phenylbutazone (colloquially known as "bute") has a more potent anti-inflammatory than analgesic action. It follows the standard NSAID mechanism of COX inhibition, and concentrates in inflammatory exudates. It is cheap and commonly used in veterinary practice.

Administration of phenylbutazone with food reduces the rate of absorption. Although the drug's bioavailability remains the same, it is absorbed further down the gastro-intestinal tract than normal and plasma levels rise more slowly. Rate of metabolism varies vastly between species, and in some species (for example, the dog) phenylbutzone displays zero-order kinetics.

Phenylbutazone has caused death by aplastic anaemia in man, and since safe milk and meat residue levels cannot be established, it is banned in food producing animals. Protein losing enteropathy has been seen in horses and ponies. The drug has a low safety margin and care must be taken in equids to use the lower end of the dose range. Top range doses would lead to accumulation and toxicity.

Carprofen

Carprofen (Rimadyl) is a poor COX inhibitor, yet a potent anti-inflammatory drug. It is generally well-tolerated and can be used as a peri-operative analgesic with a reduced risk of nephrotoxicity compared to other NSAIDs.

Ketoprofen

Ketoprofen has potent anti-inflammatory, analgesic and anti-pyretic actions. In addition to its effects on COX, ketoprofen may inhibit lipoxygenase and bradykinin to have a broader mechanism of action. The main side effect is gastro-intestinal erosion.

Cinchophen

This drug has a primarily anti-inflammatory effect, though is analgesic and anti-pyretic at higher doses (similar to aspirin). Cinchophen also has uricosuric activity. Side effects include hepatotoxitiy and gastric ulceration.

Cinchophen is the main component of prednoleucotropin (PLT) tablets used for the treatment of osteoarthritis in a dog. These tablest also contain a very low dose of prednisolone, a corticosteroid.

Flunixin

Flunixin is of limited use in small animal practice due to its toxicity; however, it is commonly used in farm and equine practice. It has potent anti-inflammatory and analgesic effects and is used for such conditions as pneumonia, mastitis and endotoxic shock. Preparations are available in combination with anti-microbials (e.g. Resflor - florfenicol plus flunixin).

Fenamates

Tolfenamic acid and meclofenamic acid are the fenamates used in veterinary medicine. In addition to the usual mechanism of action, they may provide some antagonism to the prostaglandin receptor.

Oxicams

Meloxicam (Metacam) is commonly used in dogs and cats, and is now licensed in cattle, pigs and horses. It may have cartilage sparing effects in osteoarthritis, but this has only been tested under laboratory conditions. Other NSAIDs appear to be detrimental to cartilage.


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Review of NSAIDs: COX selectivity and systemic effects beyond analgesia. Budsberg, S. C.; The North American Veterinary Conference, Gainesville, USA, Small animal and exotics. Proceedings of the North American Veterinary Conference, Orlando, Florida, USA, 17-21 January, 2009, 2009, pp 1126-1128 - Full Text Article