Non-Steroidal
Anti-Inflammatory Drugs (NSAID)

General Principles

There are literally dozens of NSAID(s) on the "human" market. In general, these drugs are similar in terms of mechanism of action, therapeutic effect, toxicity but there are certainly differences among them. These notes first present the drugs as a class. Details for individual drugs are presented as an attached reference, prepared by the United States Pharmacopieal (USP) Convention's expert panel on Veterinary Medicine.

When studied in large populations and evaluated "on average" they are therapeutically indistinguishable (A particular drug is not superior for a particular disease,though toxicity may vary). Interestingly, when special studies are carried out it can be demonstrated that one drug may be superior to others for a particular patient.

• These choices are based on years of use of these drugs at particular doses OR on the manufacturer's label.
• For most disorders (and species), only a limited number of drugs have even been evaluated for a particular disorder. (e.g., Flunixin meglumine has a positive effect on endotoxemia. However, it may not be the BEST drug and the dose used may not be the BEST).
• Choices related to pattern of use. (e.g. Flunixin may be as good as phenylbutazone for joint pain, but used chronically produces an even higher incidence of adverse effects in horses).

Finally, because these drugs come from such a wide range of chemical classes and most are metabolized extensively, it is difficult if not impossible to extrapolate doses and clinical expectations from man to animals or between animal species. Do not use "unusual" non-steroidal anti-inflammatory drugs in veterinary patients unless you have a dose regimen from a reliable veterinary reference.

Mechanism(s) of Action

All of the non-steroidal anti-inflammatory drugs (NSAIDs) appear to share at least one common mechanism, namely inhibition of cyclo-oxygenase (COX) enzyme(s) which leads to a decrease in the synthesis of various prostaglandins and thromboxanes. Most, but not all of the NSAIDs are organic acids.

However because:

• drugs vary in selectivity for the two known isoenzymes of COX
  AND the selectivity varies by species (Carprofen appears selective in dogs but is NOT selective in people);
• drugs may or may not inhibit lipoxygenase;
• individual drugs possess a wide variety of additional activities that may or may not be important to control of pain and inflammation;

1. it is difficult to predict which drug is "best" for a particular patient.
2. it is difficult to predict which drug will be best tolerated by a particular patient.

All Drugs:

1. Inhibition of Cyclooxygenase (COX 1 and/or 2) - major mechanism of action of all available NSAIDs - mode of inhibition varies with each of the chemical categories - COX 1 - constitutive production (GI mucosa) - COX 2 - inducible (inflammation) production

Some drugs:

2. Inhibition of Phospholipase A - major mechanism for effects of glucocorticoids on prostaglandin production
3. Inhibition of lipooxygenase - in addition to cyclooxygenase inhibition; probably ketoprofen, certainly tepoxalin
4. Inhibition of Specific Mediator Synthesis - e.g. thromboxane synthetase inhibitors; in development

Miscellaneous drugs: not all drugs, not all patients:

1. Modify Mediator Actions - e.g. reduces leukocyte migration factor production &/or activity
2. Direct Actions Unrelated to Eicosanoids (vary widely between NSAIDs)

   Cell-membrane Processes

   • NADPH oxidase activity in neutrophils
   • phospholipase C activity in macrophages Proteoglycan (reduced) synthesis
   • by chondrocytes
   • Transmembrane ion fluxes
   • Cell to cell binding

Pharmacokinetics

General information

All relatively small volume of distribution (0.15 -0.3 L/kg) because they have relatively high protein binding (70-99%) therefore:

• hepatic metabolism predominates, is limited by enzyme capacity rather than blood flow regulated
• NSAID dosing in one species is UNLIKELY to be correct for another. (e.g., Human NSAID doses are OFTEN dangerous to dogs.)
• LOTS of drug interaction potential
• (however...) protein binding does not restrict access by the NSAID TO inflammed tissues. Theoretically, the drug is carried to the site of inflammation on albumin.

Dosing

Dose extrapolation from one species to another is dangerous.

NSAIDs can produce mild anti-inflammatory activity, moderate analgesic activity, or potent analgesic activity depending on the dose and the agent selected. Clinical impressions of the comparative "potencies" of NSAIDs are hard to evaluate. This does not mean that I think these drugs are the same but that our assessment of their use is based on the way they're used...

• flunixin (at the labelled dosage) is generally considered a powerful analgesic. It is only used for short durations.
• phenylbutazone (at generally accepted dosage) is only modest analgesic. Higher doses are more analgesic but can only be used for short durations.
• aspirin is usually dosed for mild to moderate activity. Higher doses are more analgesic but can only be used for short durations.

Toxicity

1. Gastrointestinal - primarily due to inhibition of PGE₂ activity (produced via COX-1, mediates local increase in blood flow and maturation of gastric lining cells). Some NSAIDs are more damaging than others. Are ways to reduce the risk:
   • dose appropriately
   • pick the right drug and formulation?
     • Choose Cox-2 selective.
     • enteric coating (e.g., aspirin) - a little protection, variable absorption
     • buffers (e.g., aspirin) - a little protection, enhanced absorption
   • GI Protection?
     • PGE₂ analog - Misoprostol ® (Good evidence of efficacy)
     • Protectants (sucralfate) - no clear evidence
     • Omeprazole - no clear evidence
     • Cimetidine et al. - do not appear to be particularly effective for prevention.
   • Dogs - gastric ulcers (fatal hemorrhage, peritonitis). Carprofen and etodolac appear to be the safest. Aspirin appears comparatively safe, several other NSAIDs are more dangerous in dogs than in people.

   • Horses - gastric ulcers, colonic lesions, oral ulcers

2. Renal - toxicity POSSIBLY results from interruption of prostaglandin mediated regulation of blood flow (subject of some debate). Several conditions can worsen the effects of NSAIDs - or increase likelihood (e.g.: concurrent nephrotoxic drugs, systemic conditions - shock, dehydration, post surgical)

   Horses seem to suffer this side effect more commonly than other species.

3. Coagulation - a desirable effect in some situations but can be a problem. The effect is mediated by the elimination of TXB₂ (thromboxane) synthesis by the platelets thereby decreasing ability to adhere. With production of new platelets in the absence of NSAIDs the effect is reversed. Effect is marked even at low doses. Effect varies in intensity with NSAID (aspirin most effective/potent).

4. Allergy - bronchospasm and urticaria reported with NSAIDs; increased synthesis of leukotrienes by lipooxygenase ??

5. Hepatotoxicity - possible with ALL NSAIDs. This effect (in dogs during its first marketing year) with carprofen should not have been a surprise.
6. Blood dyscrasia - probably unique to phenylbutazone (chemical structure). This makes extra-label use in food animals questionable (blood dyscrasia's in people consuming meat).
7. Reproductive system - some concern over effects on male fertility

Clinical Applications (all -any? - NSAIDS)

1. Fever
2. Analgesia
3. Visceral pain (flunixin)
4. musculoskeletal pain (all)
5. Endotoxemia
6. Anticoagulant (platelet) activity
7. Patent ductus arteriosus closure

Weird and wonderful anti-inflammatory agents

1. DMSO (dimethyl sulfoxide): lots of claims, very little (controlled clinical) science
   
   
   • Does everything: anti-inflammatory, anti-pyretic, anti-infective, antibiotic, etc.
   • Mechanism of action:
     • cyclooxygenase inhibitor?
     • free radical scavenger
     • undetermined?
   • Widely used as a treatment for muscular swelling, pain, and/or trauma especially in the horse (and the giant dog breeds).
   • Has reasonable (consistent anecdotal) documentation as an anti-inflammatory agent for the central nervous system.
   • Client education for handling.
   MSM (methylsulfonylmethane) ??
   
   
2. Orgotein (Palosein^®): really is a superoxide dismutase
   
   Approved for use in horses and dogs
   
   
3. Polysulfated Glycosaminoglycans or PS-GAGs (Adequan^®)
   
   Many trials have shown clinical improvement using such agents both intra-articularly and systemically (intramuscular).
   
   
4. Hyaluronic acid (both natural and synthetic analogues)
   
   Best if used early in the clinical course of a condition while there is some cartilage to protect.
   Risks of intra-articular injections. Various protocols, some involving antibiotics and/or corticosteroids.

Topic Summary (Non-steroidal anti-inflammatory drugs)

1. Large variety of compounds with similar actions but varying kinetics in different species thus varying risk of toxicity and variety of toxic effects.
2. Concurrent medical conditions or drugs administered can alter the toxic potential of these agents.
3. Dose to effect (keeping toxicity in mind) and reduce dose as much as possible for long term administration.
4. Be prepared to get some vehement opinions about how well particular NSAID's or other anti-inflammtory agents work in a particular owner's animal.