Therapeutics: musculoskeletal system

Non-steroidal anti-inflammatory drugs (NSAIDs)

* Indicates drug not licensed for this use in this species.

• Properties:
  • Anti-pyretic.
  • Anti-inflammatory.
  • Analgesic.
  • +/- Anti-endotoxemic.
  • +/- Anti-thrombotic.
• Mechanism of action: most inhibit cyclo-oxygenases (COX).
• There are three or more isoforms of COX:
  • COX-1 is mainly physiologic (gastric protection, renal blood flow, clotting activity). Some inflammatory activity has also been described in certain situations.
  • COX-2 is mainly inflammatory. Some physiologic activity has been described (renal fluid balance, uterine implantation, wound healing, including gastric ulcer healing).
  • COX-3 is a splice variant of COX-2 and is mainly central in location.
• Classification of NSAIDs:
  • Nonselective: inhibit COX-1 and COX-2 at approximately equal potencies.
  • COX-2 preferential: inhibit COX-2 to a greater degree but still have inhibition of COX-1.
  • COX-2 selective: inhibit only or predominantly COX-2 at therapeutic concentrations.
• At least one NSAID also inhibits lipoxygenase (LOX) and may be considered a dual inhibitor (COX and LOX).
• None of the NSAIDs at therapeutic levels inhibit the relevant enzyme(s) 100% continuously. There is a time course of inhibition based on tissue drug concentrations.
• Additional actions: inhibition of superoxide radical generation, blockade of lysosomal and non-lysosomal enzyme release (some have anti-bradykinin effects).
• Toxicity varies with species sensitivity, mechanism of action, and individual drug properties.
• Aspirin is unique in its covalent bonding → irreversible COX-1 inhibition.
• Most NSAIDs are well absorbed PO.
• Most NSAIDs are highly bound to plasma proteins, but still exhibit good penetration of inflammatory exudates (since plasma proteins extravasate).
• Tissue bound drug cleared more slowly than plasma protein bound drug and acts as reservoir.

Use

• For analgesic and anti-inflammatory action in acute inflammatory conditions; control of pain following surgery (some drugs comparable in this action with opioid analgesics ).
• Arthritides (osteoarthritis ).
• Aspirin used to prevent platelet aggregation in thrombo-embolic disorders. Can promote bleeding so contraindicated prior to surgery.
• Use in aged animals depends on underlying renal and liver function. As with all drugs, use of NSAIDs should include appropriate patient selection.

Side-effects

• Most commonly observed is gastrointestinal irritation (vomiting and diarrhea), with potential for ulceration, especially if concurrent use with corticosteroids.
  Do NOT give concurrently with corticosteroids
• May cause acute renal failure if administered to hypotensive/hypovolemic patients because NSAIDs block production of reno-protective prostaglandins (both COX-1 and COX-2).
• May see hepatotoxicity (rare acute hepatic necrosis reported with carprofen); may be teratogenic if given repeatedly during pregnancy.
• Acetaminophen/paracetamol *: may act by inhibition of COX-3, but this is controversial. No anti-inflammatory activity but has been used as an analgesic and anti-pyretic.
• Aspirin : classic nonselective NSAID. Tends to be irritating to GI tract. Permanently interferes with platelet thromboxane production for the life of the platelet.
• Carprofen : preferential for COX-2.
• Deracoxib : selective for COX-2; approved at two dose rates, one for surgical use and the other for osteoarthritis.
• Dipyrone *: believed to act by inhibition of COX-3. Not recommended for use in dogs with availability of safer approved products.
• Etodolac : nonselective to mildly preferential for COX-2.
• Firocoxib : selective for COX-2 with little to no COX-1 activity.
• Flunixin : nonselective NSAID, tends to have more GI irritation and renal effects, not generally recommended in dogs as there are better alternatives available.
• Ketoprofen : nonselective NSAID; approved at two dose rates, one for short-term use and the other for long-term use.
• Meloxicam : preferential for COX-2.
• Naproxen * : nonselective NSAID, tends to have more GI irritation, not recommended in dogs.
• Phenylbutazone : nonselective NSAID, tends to have more GI irritation, not recommended in dogs.
• Tepoxalin : dual COX/LOX inhibitor. Cyclo-oxygenase activity is mainly COX-1 and persists longer than LOX inhibition.
• Tolfenamic acid : nonselective NSAID. Not used in the US.
• Vedaprofen *: nonselective NSAID. Not used in the US.

Sources

Publications

Refereed papers

• Recent references from PubMed.
• Bergh M S & Budsberg S C (2005) The Coxib NSAIDs: Potential Clinical and Pharmacologic Importance in Veterinary Medicine. J Vet Intern Med 19 , 633-643.