Classification and mechanism of action

Nonsteroidal anti-inflammatory drugs are classified based upon their chemical structure into carboxylic and enolic acids. A majority of NSAIDs belong to the carboxylic acid group, while fewer are enolic acids. Many texts additionally divide NSAIDs into numerous and often confusing sub-categories based, for example, on their chemical properties, mode of action, or pharmacologic effect.⁹ This text will focus instead on their cyclooxygenase enzyme (COX)-1, -2 and -3 selectivity.

Most NSAIDs have a similar mechanism of action as well as physical and chemical properties.10–11 Nonsteroidal anti-inflammatory drugs inhibit the synthesis of prostaglandins (PGs) and thromboxanes (TBXs) from arachidonic acid by inhibiting COX. Most NSAIDs are also competitive COX antagonists; this mechanism of action of NSAIDs requires the continued presence of the active drug to exert the effect. Aspirin, however, is an irreversible antagonist that deactivates COX by acetylation. Because platelets are nonnucleated and thus do not have the capacity to synthesize new COX, ASP has a profound effect on platelet function.

There are at least two COX isomers, namely the constitutive (COX-1) found throughout the body and the so-called inducible (COX-2) isoforms.⁹ The COX-1 isomer is the ‘housekeeping’ enzyme responsible for basal synthesis of PGs necessary for physiologic functions, including maintenance of vasomotor tone (intestinal mucosal and renal blood flow), prevention of platelet aggregation and adhesion and maintenance of gastric cytoprotection.⁹ The COX-2 isomer is responsible for increased eicosanoid synthesis associated with inflammation and is induced by lipopolysaccaride (LPS), cytokines and other inflammatory mediators. However, the ‘good’ COX-1 versus ‘bad’ COX-2 dichotomy has proved overly simplistic. COX-2 has been shown to exert its own physiological effects, for instance in regulating renal blood flow¹² and GI mucosal integrity, especially in ulcer healing.^13–14 A third COX isoform, sensitive to acetaminophen and referred to as COX-3, COX 1b or COX-1 variant (because of its similarity to COX-1) has also been identified in some species including the dog.¹³ The affinity for the COX isoforms varies among NSAIDs. Some are more potent inhibitors of COX-1, while some are relatively equipotent for their effects on COX-1 and COX-2, and others have a greater selectivity for COX-2. The COX-2/COX-1 ratio is a convention used to reflect the relative selectivity of an NSAID for the COX isomers.⁹ Unfortunately, the convention can be confusing to the reader because the numerator/denominator values (COX-2/COX-1) actually reflect the IC₅₀ for each isomer. The IC₅₀ represents the concentration of a drug that is required for 50% inhibition in vitro.^9b Hence, an NSAID with a COX-2/COX-1 ratio <1 is preferable in order to maximize the anti-inflammatory effects of the NSAID while minimizing the potential for toxic side effects. With that in mind, an array of COX-2 specific inhibitors, known as coxibs, have been developed and some have been used in horses. Currently, firocoxib (FCB) is the only COX-2 selective drug labeled for use in horses in the United States, while meloxicam (MLX), which is somewhat selective for COX-2, is approved for use in horses in Europe.¹⁵ The concentration of firocoxib required to inhibit 50% of COX-1 activity in horses is reported to be >640 times that required to inhibit 50% of COX-2 activity.¹⁶ Furthermore, concentrations of firocoxib that inhibit 80% and 50% of COX-2 activity in vitro (67 and 30 ng/mL, respectively) are readily achievable in equine plasma following oral administration at the label dose of 0.1 mg/kg.¹⁷ The relative potency of the COX-2 versus COX-1 drugs as analgesics when administered at their approved dose rates has been the subject of debate. However, in a study that compared the efficacy and safety of FCB (0.1 mg/kg, PO, SID) and PBZ (~4.4 mg/kg, PO, SID) paste formulations administered for 12–16 days to 253 horses with chronic arthritis, the proportion of horses clinically improved on day 14 for the FCB group (104/123 [84.6%]) was not significantly different from the proportion for the PBZ group (103/119 [86.6%].¹⁸ In a second study, when FCB was administered as an oral paste (0.1 mg/kg, PO SID) for 14 days to 390 horses afflicted with osteoarthritis, improvement was reported in approximately 80% by day 14.¹⁹ Finally, when oral MLX (0.6 mg/kg) was administered to horses with induced intercarpal joint synovitis, lameness and joint effusion was alleviated compared to placebo-treated joints, as were synovial fluid biomarkers (PGE2, substance P, bradykinin, MMP), and some turnover markers of aggrecan (GAG) and type II collagen (CPII, C2C).²⁰

Peak plasma concentrations and the onset of action for NSAIDs after oral administration varies with the timing of administration relative to eating. Mean time to peak plasma concentration for PBZ (4.4 mg/kg PO) in ponies with access to hay was delayed 6 to 12 hours, compared with fasted ponies.²¹ Phenylbutazone and other NSAIDs appear to bind to hay and other digesta, thus delaying time to peak plasma concentration. Fermentative digestion of roughage in the large intestine releases the bound drug, which possibly contributes to the propensity of NSAIDs to cause ulcerative disease in the large intestine.¹⁰ The time to reach peak plasma concentration and the elimination half-life can be dramatically prolonged by the timing of administration relative to feeding. This has important clinical implications with regard to the therapeutic efficacy of an orally-administered NSAID as well as with potential problems related to horses in sanctioned competitive events.

There is conflicting data regarding the effects of feeding versus fasting on the absorption of MFA.9,22 Horses with free access to feed had delayed absorption, decreased maximal plasma concentration, and delayed time to peak concentration, compared with fasted horses, administered FLM. Although it may not be practical, NSAIDs should be administered to horses that have not eaten for at least two hours before, and are withheld from feeding for two hours after, dosing in order to control absorption, time to peak plasma concentration, and elimination half-life.

Drug interactions

Concurrent administration of chloramphenicol reduces the clearance and increases the half-life of PBZ, which may accentuate both therapeutic and toxic effects. A single dose (25 mg/kg IV) of chloramphenicol prior to PBZ administration resulted in a significant decrease in the elimination rate, and this effect was accentuated by additional dosing of chloramphenicol.³⁶ Rifampin induces hepatic biotransformation processes and has been shown to increase the elimination rate of PBZ in horses.³⁶

There are anecdotal reports that when PBZ is administered to horses anesthetized with thiobarbiturates increased depth and duration of anesthesia may occur due to competitive plasma protein binding.37–38 A study evaluating administration of PBZ (8.8 mg/kg IV) nine minutes after thiamylal (11 mg/kg IV) demonstrated no effects of PBZ on thiamylal pharmacokinetic parameters or depth or duration of anesthesia.³⁹ However, there were changes in PBZ pharmacokinetics, including increased serum concentrations and decreased percentage protein bound PBZ. In another study, administration of PBZ (6.6 mg/kg IV) for four days prior to thiamylal anesthesia did not have a significant effect on recumbency time.³⁶ Therefore, it seems unlikely that perianesthetic administration of PBZ would alter the intensity or duration of anesthesia. It also seems unlikely that thiamylal administration would have a clinically important effect on the disposition of PBZ.

A study evaluating the pharmacokinetics of steady-state PBZ and single bolus gentamicin administered together revealed that gentamicin pharmacokinetics are altered by concomitant PBZ therapy, however, no effect of gentamicin was found on the pharmacokinetics of PBZ.⁴⁰ Gentamicin was administered as a 2.2 mg/kg IV bolus on the fourth day of once daily treatment with PBZ (4.4 mg/kg IV). Phenylbutazone induced a 49% increase in the rate of gentamicin return to the central compartment from peripheral tissues and the half-life and volume of distribution of gentamicin decreased 23% and 26%, respectively. There were no changes in PBZ pharmacokinetics induced by gentamicin. Because PBZ induces changes in the rate and extent of distribution and elimination of gentamicin, caution should be exercised when using this drug combination in horses.

Dosage regimen

The dose, interval, and route of administration for NSAIDs commonly used in horses are given in Table 23.1.^{11,22,29,41–47}

Therapeutic uses

NSAIDs are indicated in horses with inflammatory conditions of the musculoskeletal system including tendonitis, myositis, desmitis, laminitis, osteoarthritis, synovitis/tenosynovitis, osteitis/osteomyelitis, septic arthritis, and surgically- or traumatically-induced injury. Primary functions include limiting the inflammatory response to injury and concomitantly alleviating associated pain. NSAIDs are similarly administered around the time of surgery to control postoperative pain, fever and prevent excessive edema formation.

Although the mechanism of action is the same, there are apparent differences in the efficacy of different NSAIDs depending upon the type of condition being treated. For example, clinical and experimental data suggest PBZ is more efficacious in providing analgesia for most horses with musculoskeletal disease, whereas FLM is more effective in providing visceral analgesia in horses with colic.⁴⁸ These differences in effect may be due to the specificity of certain NSAIDs for different COX isomers or for COX within different tissues. Ketoprofen is reported to be effective in decreasing inflammation and pain associated with musculoskeletal disease and colic.^49–51

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