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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 inhibition.
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==
==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.
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.
==Actions==
==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.
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.
==Pharmacokinetic Considerations==
==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.
Pharmacokinetics for NSAIDs differ greatly between species, meaning that data from one species cannot be used to reliably calculate a dose for another.
==Side Effects and Contraindications==
==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.
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.
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.
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.
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.
===Drug Interactions===
===Drug Interactions===
The concurrent use of two COX inhibitors will result in both additive efficacy and toxicity.
The concurrent use of two COX inhibitors will result in both additive efficacy and toxicity.
==Drugs in This Group==
==Drugs in This Group==
===Aspirin===
===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 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.
===[[Paracetamol]]===
===[[Paracetamol]]===
===Phenylbutazone===
===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.
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.
===Carprofen===
===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 reduce risk of nephrotoxicity compared to other NSAIDs.
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 reduce risk of nephrotoxicity compared to other NSAIDs.
===Ketoprofen===
===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.
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===
===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.
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.
===Flunixin===
===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).
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===
===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.
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===
===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.
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.