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NSAIDs

• NSAID stands for non-steroidal anti-inflammatory drug.
• These drugs impact the action of inflammatory mediators.
• Willow bark was used traditionally, and Bayer refined it into aspirin in 1898.

Inflammation

• Inflammation is the body's protective response to harmful stimuli, such as injury or micro-organisms.
• Acute inflammation presents five signs: redness, heat, swelling, pain, and loss of function.

How NSAIDs Work

• NSAIDs block the cyclooxygenase (COX) enzyme.
• The "pain pathway" involves modulation, receptor, peripheral nerves, spinal cord, transmission, and the brain.
• Arachidonic acid is released when cell walls are damaged.
• COX-1 is constitutive and leads to the production of prostaglandins.
  • Prostaglandins provide GI mucosal protection and renal blood flow regulation.
• COX-2 is inducible and also leads to the production of prostaglandins.
  • These prostaglandins cause pain, fever, and inflammation.
• Lipoxygenase produces leukotrienes.

Prostaglandins Involved With Inflammation

• PGE2 leads to vasodilation, pain (sensitizes neurons), and fever (in the hypothalamus).
• PGI2 (also called prostacyclin) results in vasodilation and pain.

NSAIDs Metabolism

• Metabolism varies widely across classes.
• NSAIDs generally have good oral and parenteral uptake and high protein binding.
• Most undergo hepatic metabolism, and metabolites are excreted by the kidneys.
• Some undergo enterohepatic recycling.

Why Use NSAIDs?

• NSAIDs, antihistamines, and glucocorticoids are all anti-inflammatory but act against different inflammatory processes and mediators.
• Arachidonic acid (AA) is released when the cell membrane is damaged.
• Cyclooxygenase (COX) and lipoxygenase act on AA to produce prostaglandins and leukotrienes, which then produce further downstream products.
• NSAIDs block the action of COX, also blocking lipoxygenase.

Indications for NSAIDs

• NSAIDs are indicated for inflammatory conditions, injuries, and surgery.
• Inflammatory conditions typically have "itis" at the end of the word.
• NSAIDs may be useful in mastitis, metritis, tendonitis, osteoarthritis, gastroenteritis, gastritis, colitis, bronchitis, and gingivitis.
• NSAIDs address localized swelling, redness, heat, pain, and loss of function.
• They also address generalized systemic effects like pyrexia, malaise, and generalized pain.
• NSAIDs are not effective for skin conditions; glucorticoids or antihistamines are preferable.
• Bites, lacerations, tendon or muscle strains, ligament sprains, bruising, and fractures may benefit from NSAIDs.
• When used post-injury, swelling, redness, heat, pain, and loss of function at and around the injury site are likely.
• Surgery patients are frequently in pain when referred for surgery; it's rare for surgery to be pain-free during or immediately afterward.
• NSAIDs can be valuable for elective surgeries such as neutering, or non-elective/emergency surgeries, such as a caesarean operation.
• Achieving complete (100%) pain relief when using (almost all) painkillers, including NSAIDs, is almost impossible.

NSAIDs Licensed in the UK

• NSAIDs are licensed by name and species indication.

Species Differences

• Biotransformation and elimination half-lives vary significantly by species and sometimes by breed.
• Dosage extrapolation from one species to another is unsafe.
• Most NSAIDs are highly protein bound and bio-transformed in the liver into inactive metabolites.
• Excretion occurs via the kidneys through glomerular filtration and tubular secretion, or via the bile.

Side Effects

• GI side effects, such as ulceration and bleeding are common across species.
• Presentation of side effects varies.
• Species that can vomit, such as dogs and cats, often experience vomiting.
• All species can display signs of malaise, abdominal pain, and diarrhea.
• Blood may be present in the faeces, either frank or digested.

Contraindications

• Absolute contraindications mean that NSAIDs must not be used in an animal or species because adverse events occur.
• Relative contraindications represent considerations before prescribing NSAIDs generally or specific NSAIDs.
  • These relative contraindications don't always relate to the individual animal's safety.
• Licensed drugs should be used for the indication in the species.
• The challenge involves knowing which unlicensed drugs are okay to use "off label" and which could be harmful.
• If unsure if a product is safe to use 'off label', avoid it.
• Cats are particularly sensitive to NSAIDs; only licensed products should be used.
• Patients may have conditions preventing the administration of a specific drug.
  • For example, NSAIDs shouldn't be used in cats suffering from gastrointestinal irritation, hemorrhage, impaired hepatic, cardiac, or renal function and hemorrhagic disorders.
• Phenylbutazone must never be given to a food-producing animal.
• Combining NSAIDs should be avoided.
• If one NSAID proves ineffective and an alternative agent is to be administered, a washout period is advised
  • While no data exists for optimum wash-out periods, 3-5 days is perceived to be safe for most.
• Glucocorticoids are prescribed for inflammatory and allergic conditions.
• Topical administration falls under this prohibition.
• Skin cases benefit more from corticosteroids, because NSAIDs do not work effectively for skin inflammation and do not act against allergy.

Relative Contraindications

• In food-producing animals, consider meat/milk/egg withdrawal periods.
• The relative sporting animal contraindications involve clean sport: NSAIDs aren't inherently performance-enhancing.
• The main issue is related to animal welfare; animals shouldn't compete if NSAIDs are necessary for them to be able to compete.
• Note that some NSAIDs have extended excretion times, potentially impacting return to sport even after injury healing such meloxicam.

Alternatives to NSAIDs

• For pain from injuries and surgery, use a different class of painkiller (lectures on pain will discuss)
• Use antihistamines or glucocorticoids for inflammation.

NSAIDs in Small Animal Practice

• A number of NSAIDs are licensed for dogs.
• Fewer NSAIDs are licensed for cats.
• Only one NSAID is licensed for Guinea pigs.
• Other species depend on the cascade.
• Osteoarthritis is commonly treated with NSAIDs in dogs and cats.
• These are used after all surgery unless specifically contraindicated and for wounds and injuries,.

NSAIDs in Equine Practice

• Phenylbutazone, suxibuzone, flunixin and meloxicam are the most commonly used NSAIDs.
• Cost of medications can be an issue, given the size of horses.
• Long-term musculoskeletal issues, like laminitis and osteoarthritis, are treated.
• Colic (with or without surgery) is addressed for pain relief and antiendotoxic qualities,.
• NSAIDs are useful Before, during and after surgery like dental extractions.
• Horses treated with Phenylbutazone must never be used for human consumption.

NSAIDs in Food-Producing (Mammalian) Species

• Only pain relief available can be used for food producing species.
• Sheep and goats use falls under the cascade.
• Ruminants can only be treated using injections due to issues with oral absorption of NSAIDs.
• Pigs can be treated using oral and injectable formulas.
• NSAIDs are useful for anti-inflammatory effects in pneumonia, mastitis, metritis and all other ‘itis' seen on farms.
• These are also prescribed for anti pyrexia for any random pyrexia not diagnosed as above.
• NSAIDs are useful After all surgeries and lameness cases, also arthritis in older pet farm animals.
• Always check the withdrawal periods for milk and meat (different for different NSAIDs).
• Phenylbutazone should never be used.

Practice questions

• Maintain blood pressure during anesthesia if NSAIDs are given preoperatively to dogs and cats to protect the kidneys.
• Cyclooxygenase is the enzyme inhibited by most NSAIDs.
• NSAIDs are prescribed to horses for acute and chronic pain, and have anti-endotoxic properties.
• Inform the owner about meat and milk withdrawal times when administering NSAIDs to farm species.