Nonsteroidal Antiinflammatory Drugs: A Review
The increasing use of nonsteroidal antiinflammatory drugs (NSAIDs) in small animals has resulted in the development of new and innovative additions to this class of drugs. Examples of NSAIDs now available for use in small animals include aspirin, etodolac, carprofen, ketoprofen, meloxicam, deracoxib, and tepoxalin. The purposes of this article are to review the pathophysiology of prostaglandin synthesis and inhibition, the mechanisms of action, pharmacokinetics, pharmacological effects, and potential adverse reactions of aspirin and the newly released NSAIDs.
Introduction
Prostaglandins belong to a group of compounds known as eicosanoids.1 Eicosanoids are breakdown products of the polyunsaturated fatty acids (e.g., arachidonic acid) of the plasmalemmal phospholipids. When cell membranes are damaged, arachidonic acid is liberated into the cytoplasm where it serves as a substrate for the lipoxygenases (e.g., 5-lipoxygenase), cyclooxygenases (e.g., prostaglandin synthase, prostaglandin H synthase), and other enzymes [see Figure].1–3
Although there are three mammalian lipoxygenases, the one with the most clinical significance is 5-lipoxygenase.3 It is 5-lipoxygenase that is responsible for the conversion of arachidonic acid to 5-hydroperoxy-eicosatetraenoic acid, which is then enzymatically converted to leukotriene A4 (LTA4).3 Leukotriene A4 is the precursor molecule for the other leukotrienes and can be enzymatically converted to leukotriene B4 (LTB4), which attracts many cells of myeloid origin.3 Clinically, the leukotrienes are associated with a vigorous inflammatory response.3 Most notably, leukotrienes increase microvascular permeability and are potent chemotactic agents triggering neutrophil clumping, neutrophil degranulation, and neutrophil-endothelial adhesion.3
Cyclooxygenase enzymes oxygenate arachidonic acid, creating unstable prostaglandin endoperoxide prostaglandin G2 (PGG2).1 Successive peroxidase reactions occur first in the production of prostaglandin H2 (PGH2) and eventually in the production of specific prostaglandin end-products.1 The prostaglandins produced are the result of the action of the specific isomerase enzymes (i.e., cyclooxygenase 1 [COX-1] and cyclooxygenase 2 [COX-2]).4
Cyclooxygenase 1-related prostaglandins (i.e., constitutive prostaglandins) are produced by many tissues and participate in the maintenance of a variety of physiological effects (e.g., protection of gastrointestinal [GI] mucosa, maintenance of renal blood flow, hemostasis).1,3,5 Cyclooxygenase 2, on the other hand, is the isoform primarily responsible for the production of inducible prostaglandins [see Figure].5 As such, COX-2-related prostaglandins are considered to be “nonphysiologic” and represent a clinically and therapeutically relevant group of compounds primarily involved in inflammation. Vasodilatation, changes in capillary permeability, potentiation of other chemical mediators of inflammation (e.g., histamine), chemotaxis, and hyperalgesia are all aspects of inflammation that are initiated and perpetuated by the presence of COX-2-related prostaglandins.1,4 It is important to note that COX-1 and COX-2 are also structurally distinct.3 They have different numbers of amino acids and sequences, as well as different morphologies.3 A smaller valine at the 523 position of COX-2 gives access to a “side pocket” unique to COX-2.3 This side pocket is exploited as the binding site for NSAIDs that preferentially bind with COX-2.3
Mechanisms of Action
Nonsteroidal antiinflammatory drugs block the production of prostaglandin by binding to and obstructing the action of cyclooxygenase, an interaction that is contingent upon both the drug and dose chosen.1,6 The therapeutic, toxic, and antiinflammatory properties of different NSAIDs are directly related to the amount and type of prostaglandin production that is impeded.4 Recently, concerns have arisen over the fate of arachidonic acid in animals being treated with NSAIDs. It is suspected that arachidonic acid not metabolized to prostaglandin by the COX enzymes may enter other metabolic pathways (i.e., the lipoxygenase pathway), so the use of COX inhibitors may result in overrepresentation of the proinflammatory effects of leukotrienes.3 This possibility is of particular concern, because the end-products of the lipoxygenase pathway (i.e., leukotrienes) may play an integral role in inflammation and may contribute to some of the side effects associated with NSAIDs.3
Based on the nature and physiological actions of COX-1 and COX-2, the NSAIDs that preferentially block the production of COX-2-related prostaglandins may be clinically superior to those with less COX-2 selectivity. Nonsteroidal antiinflammatory drugs that inhibit COX-2 may be more desirable, because they inhibit the formation of COX-2 prostaglandins that are responsible for the clinical signs associated with inflammation, and because they do not have as much effect on the COX-1 prostaglandins, which have many homeostatic properties.1,7,8
The specificity of a drug for a given isoform of COX is typically reported as a ratio. A COX-2:COX-1 ratio <1.0 has traditionally been sought, as this ratio indicates that a given NSAID preferentially inhibits COX-2 (i.e., less drug is required to inhibit COX-2 than is needed to inhibit COX-1 activity).1,7,8 Much of the ongoing research on NSAIDs has been aimed at the development of COX-2 selective drugs.
Care must be taken when interpreting COX ratios, as there is much inconsistency in the format of the ratio, its derivation, and the clinical applicability of the information presented. For example, it is not uncommon for a COX ratio to be reported as COX-1:COX-2 rather than COX-2:COX-1. If information is presented in the form of a COX-1:COX-2 ratio, the ratio must be >1.0 in order to achieve COX-2 selectivity. Additionally, while in vitro studies typically use thromboxane B2 (TxB2) and prostaglandin E2 (PGE2) analyses to quantitate a drug’s inhibitory concentration for COX-1 and COX-2, respectively, the methods used to induce PGE2 synthesis via COX-2 vary greatly from study to study.9 This variation makes direct comparisons between studies difficult. Similarly, there is evidence to suggest that the in vitro COX selectivity of a given drug may vary among species.9 For example, Streppa et al. found etodolac to be COX-1 selective in dogs, but the drug was previously described in some human studies to be COX-2 selective.9,10 Cross-species discrepancies often make it difficult to project a given NSAID’s COX profile, so the decision to use a specific drug should be tempered by an understanding of its mechanisms of action, pharmacokinetics, potential adverse effects, and the animal’s response to therapy.
Recent research has been directed at determining whether cyclooxygenase inhibition is solely responsible for the antiinflammatory activities of the NSAIDs. The chemical structure of NSAIDs allows them to partition (even at low concentrations) into leukocyte cell membranes where they change membrane viscosity.2 At higher concentrations, it appears that NSAIDs interact with plasmalemmal proteins, disrupting the response of leukocytes to extracellular signals by interfering with G-proteins.2 Other research has indicated that NSAIDs decrease the adhesion of neutrophils and may interfere with other aspects of neutrophil function.11 Researchers have also found that NSAIDs may have immunomodulatory effects via alteration of prostaglandin production.11 Certain NSAIDs may increase cellular immunity via depression of PGE2 synthesis, which dampens the immune response.11
Pharmacokinetics
Nonsteroidal antiinflammatory drugs have relatively uniform pharmacokinetic properties. The chemical nature of the drugs (i.e., weak acids) allows for very efficient absorption following enteral administration; however, it should be noted that individual drugs vary in their absorption when given with or without food.1 Once absorbed, NSAIDs are highly protein bound.1,12 Because it is unbound drug that is of therapeutic importance, animals with abnormal serum albumin concentrations require careful adjustment of dosages.1,12 Although it is possible for hypoalbuminemic animals to experience NSAID toxicity even if they are given a normal dose, in most cases this is not a concern, as unbound drug is quickly metabolized or excreted.12
Most NSAIDs undergo hepatic metabolism prior to elimination via urinary excretion. Some undergo extensive enterohepatic recirculation, and others are unchanged when eliminated in the urine.1,13 Because of the volume of distribution of NSAIDs and because of age-related differences in metabolic capabilities, both pediatric and geriatric animals may require significant dosage reductions.12
Adverse Reactions
The most predictable and serious adverse effects associated with NSAIDs occur in the GI tract. Gastrointestinal perforation, ulceration, and bleeding have been associated with NSAID-induced depression of normal PGE2-mediated, mucosal protective mechanisms (e.g., bicarbonate and mucous secretion, epithelialization, and maintenance of mucosal blood flow).3 Because the maintenance of GI mucosal integrity is largely the result of COX-1 activity, it is logical that COX-2 selective NSAIDs are associated with fewer GI complications. Recent research has established that the selective neutralization of PGE2 by a COX-2 inhibitor decreased prostaglandin production at sites of inflammation, but it did not inhibit prostaglandin production in the upper GI tract and was not associated with gastric ulceration even at 100 × the effective dose.14,15 Additionally, COX-2 selective NSAIDs have produced fewer GI ulcerations (on endoscopy) than other NSAIDs.16 However, COX-2 was recently found to be induced at sites of gastric injury or ulceration, and the use of COX-2 selective drugs increased the amount of time it took for gastric ulcerations to heal.17 Kirchner et al. have suggested that a potential factor that may predispose animals to GI ulceration from NSAIDs is the unchecked activity of the lipoxygenase pathway for arachidonic acid metabolism.18 These authors reported that many cases of NSAID-related GI ulceration had high levels of both lipid peroxides and LTB4 in the gastric mucosa.18 The proinflammatory effects of LTB4 may explain the increased mucosal inflammation and ulceration seen.18 Recently, the role of COX-2 in GI mucosal protection has been further scrutinized. Wallace et al. noted that for NSAIDs to produce significant GI mucosal damage, both COX-1 and COX-2 must be inhibited.19 In fact, the selective inhibition of only one COX isoform did not result in significant gastric damage.19 This finding led to the assertion that COX-2 may contribute more significantly to mucosal defense than had previously been suspected. Interestingly, because of the unique interaction of aspirin with the COX isoforms, specifically with COX-2, a gastroprotective molecule known as aspirin-triggered lipoxin is formed.20,21 Aspirin-triggered lipoxin is a potent antiinflammatory agent, and via this molecule, COX-2 may play an integral role in GI protection, especially during aspirin usage.22
Nonsteroidal antiinflammatory drugs may cause nephropathy, especially with chronic use. Maintenance of renal blood flow in the face of increased arterial tone is accomplished by the vasodilatory effects of prostaglandin.16 Immunohistochemical studies have demonstrated COX-1 prostaglandin activity in many renal tissues, including the arterioles, collecting ducts, and glomeruli.23 Surprisingly, the constitutive expression of COX-2 has recently been described in the cells of the macula densa.24 In the macula densa, the production of COX-2-related prostaglandins has been shown to increase in animals following salt and water restriction, thereby indicating that renal physiology may rely on the presence of both COX-1 and COX-2-related prostaglandins.24 The full implication of the constitutive expression of COX-2 in the kidneys is yet to be elucidated, but there is particular concern that COX-2 selective agents could impair compensated renal function in animals that are either volume depleted or have congestive heart failure.25 Groups at risk include extremely old or young animals, animals with low-volume circulatory states (e.g., late-stage heart failure, renal failure, hypotension, hypovolemia), and animals with hepatic insufficiency or failure. The concurrent use of other nephrotoxic drugs increases the risk of NSAID-related nephropathy.
Because NSAIDs have the potential to produce several untoward side effects, the concurrent use of other NSAIDs or corticosteroids should be strongly discouraged.26,27 In a case study of 1415 people, the concomitant use of corticosteroids and NSAIDs was associated with a 15% greater risk of peptic ulceration than for patients receiving neither type of medication.27 In the authors’ experience, animals that are given combinations of NSAIDs or NSAIDs and corticosteroids have a higher incidence of gastroenteritis, GI ulceration, and GI perforation.
The use of aspirin as an antithrombotic agent has become commonplace in humans, based on the inhibition of COX-1 production of thromboxane.1 Inappropriate dosing or administration of aspirin may result in unintentional or exaggerated antithrombosis. Decreased platelet aggregation can be both a beneficial and negative side effect of NSAID use. Once damaged by NSAIDs, platelet cyclooxygenase cannot be repaired or replaced (i.e., nonselective NSAIDs permanently and irreversibly damage platelets).1 Concerns about potential prothrombotic effects of COX-2 selective NSAIDs have been raised. It seems that the selective inhibition of COX-2 interferes with the antithrombotic activity of prostacyclin and allows the unchecked activity of thromboxane; therefore, COX-2 selective NSAIDs may increase the tendency toward thrombosis.16
It is vital to remember that inflammation is a necessary part of tissue healing, which has prompted researchers to investigate the potential adverse effects of NSAIDs on the healing process. For example, prostaglandins are important regulators of bone metabolism. In bone, osteoblasts appear to be the major source of prostaglandin, and the presence of prostaglandin strongly promotes bone formation.28 In a recent study, fracture healing was slowed in animals receiving NSAIDs.16 This study also proposed that fracture healing may be further slowed in animals receiving COX-2 selective NSAIDs.16
Aspirin
Aspirin (i.e., acetylsalicylic acid) was one of the first nonsteroidal antiinflammatory drugs discovered. It has traditionally been used for its analgesic, antipyretic, and anticoagulative effects. Aspirin is a nonselective inhibitor of cyclooxygenase. It is the only known NSAID that prevents arachidonic acid from accessing the core of the COX enzymes by covalently modifying amino acids in the COX isoforms.20 As expected, by inhibiting the COX enzymes, aspirin reduces the endogenous production of prostaglandins. Because aspirin also inhibits thromboxane formation, it is a potent anticoagulant. As mentioned above, the reduction of platelet thromboxane induced by aspirin is permanent and irreversible.29,30 Aspirin may be of particular use as an anticoagulant in some hypoalbuminemic animals, because hypercoagulable states associated with protein-losing glomerulonephropathy can have decreased circulating volumes of antithrombin III that render heparin useless as an anticoagulant.
Contraindications and Warnings
Although aspirin is relatively safe for use in both dogs and cats, it does have some associated toxicities. Aspirin is metabolized primarily via the hepatic enzyme glucuronyl transferase.30 Cats are deficient in this enzyme, which prolongs the drug half-life and predisposes cats to salicylate intoxication, especially with repeated administration. Salicylate and its metabolites are excreted in the urine both by filtration and active tubular secretion.31,32 Dogs are predisposed to adverse GI side effects, such as ulceration and bleeding.30
The use of aspirin in animals that are hypersensitive to the drug is contraindicated. Other contraindications include bleeding disorders (e.g., von Willebrand’s disease, hemophilia, liver failure, rodenticide intoxication, etc.), renal insufficiency or failure, GI ulceration or perforation, and asthma.30 Because of its route of metabolism and excretion, aspirin should be used with caution in animals with either hepatic or renal dysfunction. Animals on chronic aspirin therapy should have the drug discontinued at least 1 week prior to surgery.30 This precaution lessens the likelihood of intraoperative bleeding arising from aspirin’s antiplatelet effects. Of special note is aspirin’s ability to delay parturition (presumably through the decreased production of prostaglandin F2α [PGF2α]), which makes late gestation a contraindication for aspirin therapy.30
Side effects of aspirin are usually associated with GI upset. Animals may exhibit signs of diarrhea, vomiting, or anorexia even at therapeutic doses. It is possible for GI ulceration to result in severe intestinal bleeding with secondary anemia, hypoproteinemia, and an increase in serum urea nitrogen from increased protein digestion.30 In dogs, GI signs are anecdotally worse when treatment is with plain aspirin rather than with buffered aspirin or enteric-coated aspirin.
Signs of overdosage typically include malaise, emesis, anorexia, hyperthermia, and increased respiratory rate.30 Treatment of overdosage consists of induction of emesis (if intoxication is acute), administration of activated charcoal and a cathartic, or the use of gastric lavage.30,33 Intravenous fluids are started to induce diuresis, and alkalinizing agents are given to correct the accompanying metabolic acidosis. Additional measures such as peritoneal dialysis or administration of mannitol may be indicated, depending on the severity of the intoxication.30,34
Drug Interactions
Many drug interactions must be considered when using aspirin. The concurrent use of corticosteroids should be avoided, because this combination significantly increases the risk of damage to the GI epithelium. Concurrent use of alkalinizing agents (e.g., acetazolamide) increases excretion of aspirin, and carbonic anhydrase inhibitors may cause an increase in the transport of aspirin into the central nervous system.30 Conversely, urinary acidifiers decrease the rate of aspirin excretion.30 Drugs that increase cytochrome p450 enzyme activity in the liver (e.g., barbiturates) may be associated with a decrease in the half-life of aspirin.30 Because aspirin may decrease glomerular filtration rate via its effects on vascular tone in the renal medulla, the concurrent use of nephrotoxic antibiotics (e.g., aminoglycosides) is not recommended.30
Etodolac
Etodolac is an indole acetic acid derivative that is commonly used for its analgesic, antiinflammatory, and antipyretic properties. Etodolac inhibits both COX-1 and COX-2, albeit to differing degrees.30 Some reports indicate that etodolac preferentially inhibits COX-2, while others indicate that etodolac primarily inhibits COX-1.9,35 These contradictory findings may indicate species specificity for etodolac and may limit the ability to make interspecies correlations.
In addition to inhibiting the production of inducible prostaglandins, some of the antiinflammatory effects of etodolac are attributed to an interference with macrophage chemotaxis.36 Etodolac is absorbed quickly after oral administration, with maximum blood concentrations and onset of action occurring within 30 to 60 minutes in most cases.37 Etodolac is primarily removed from the body through biliary excretion; however, it does undergo enterohepatic recirculation.30 Enterohepatic recirculation gives etodolac a long serum half-life (i.e., 9.7 to 14.4 hours) and allows it to be administered once daily.38
Contraindications and Warnings
Previously identified hypersensitivity to etodolac is a contraindication for its use. Etodolac should be used with caution in animals with hepatic, renal, or hematological dysfunction.30 Because etodolac is metabolized and excreted primarily by the liver, its use in animals with hepatic insufficiency or failure should be done very carefully, with close attention to the dosage administered and with careful monitoring of the animal.39 Because etodolac has not been evaluated in pregnant or lactating bitches or in dogs <12 months of age, its use in these animals is not recommended.a
Etodolac has been associated with GI upset (e.g., vomiting, diarrhea, anorexia) and hypoproteinemia.38 Etodolac may cause gastric ulceration, especially at higher-than-recommended doses.b In a recent retrospective study, Klauss et al. found that etodolac caused keratoconjunctivitis sicca in dogs.40 In this study, a short duration of treatment was associated with improved outcome, so tear production should be monitored closely in dogs before and during treatment with etodolac.40
Overdosage with etodolac has been reported in dogs receiving 25 to 80 mg/kg for 3 to 12 months.b In these animals, clinical signs were consistent with GI upset and ulceration.b If an animal is overdosed with etodolac, emesis is induced (if intoxication is acute), and administration of activated charcoal and a cathartic is recommended.41 Intravenous fluids are also given to induce diuresis, and gastric cytoprotective agents (e.g., sucralfate) may be considered.41
Drug Interactions
The concurrent use of drugs potentially toxic to the GI tract or kidneys (e.g., corticosteroids or other NSAIDs) is not recommended with etodolac.a The activity of etodolac has not been evaluated with the concomitant use of highly protein-bound drugs, thus requiring careful observation of the animal in such settings.a Because etodolac decreases the urinary excretion of some drugs (e.g., digoxin), it may increase their risk of toxicity.41
Carprofen
Carprofen is a propionic-acid derivative approved in the United States for use in dogs; it is available in oral and injectable forms.42 The analgesic, antiinflammatory, and antipyretic properties of the drug are the result of its reversible inhibition of COX-2 and phospholipase A2 at clinically recommended doses.43 The COX-2 selectivity of carprofen makes the oral form effective for long-term and short-term pain management, usually without the development of tolerance or a decrease in drug efficacy.44 Injectable carprofen is reserved for short-term pain management during the perioperative period and for those animals in which oral drugs are contraindicated.45 The primary difference in pharmacokinetics between the oral and injectable forms is their peak plasma concentrations after drug administration. A single oral dose of 25 mg of carprofen is rapidly absorbed and reaches maximum plasma concentrations at 16.9 μg/mL, while a single subcutaneous injection of 25 mg of carprofen results in a lower plasma peak concentration at 8.0 μg/mL.46
The route of administration of carprofen does not affect its half-life, as both oral and injectable forms have a terminal half-life of approximately 11.7±3.1 hours.47 Both of the commercially available forms of carprofen contain a mixture of the two available enantiomers, R(−) and S(+).48 The S(+) enantiomer appears to provide most of the antiinflammatory effects, because the R(−) enantiomer is eliminated from the blood and secreted in the bile roughly two times faster than the S(+) enantiomer.48 Like other NSAIDs, carprofen is highly protein bound in the blood, and it undergoes hepatic metabolism before being secreted into the duodenum by the biliary system, thus enabling enterohepatic recycling. Much of the drug is eliminated in the feces (60% to 75%), and the remaining amounts (20% to 30%) are eliminated in the urine.49
Contraindications and Warnings
Carprofen should not be used in animals with known hypersensitivity to the drug. Owners should be warned of the potential for serious side effects when dispensing carprofen. Decreased appetite, emesis, diarrhea, melena, polydipsia, polyuria, pallor, icterus, lethargy, seizures, and changes in behavior are all potential side effects described by the manufacturer.d
Some studies have indicated that when compared to other NSAIDs, carprofen appears to have fewer adverse GI side effects; this may be due to sparing of the COX-1 isoenzyme.42 However, as previously mentioned, GI signs have been reported in some animals.c
Because carprofen is metabolized by the liver and excreted in both the urine and feces, it should be used with caution in animals with hepatic or renal failure.c,d,50 Some dogs receiving carprofen have developed hepatic necrosis.51 In these cases, serum biochemical profiles revealed hypoalbuminemia and elevated alanine aminotransferase.51 Labrador retrievers appear to be predisposed to hepatic necrosis and have exhibited clinical signs approximately 20 days after initiation of carprofen therapy.51 Hepatic necrosis occurred with administration of recommended dosages in most dogs. Only a small percentage of the affected dogs received dosages above the recommended range.51 The development of hepatic necrosis in dogs may be an idiosyncratic reaction to the drug. Renal tubular necrosis may also occur in dogs with carprofen-induced hepatic toxicity.51 Clinical signs associated with hepatoxicity usually resolve with supportive care and discontinuation of carprofen.51
Because of a lack of safety information, carprofen is not recommended in animals with hemostatic abnormalities (e.g., von Willebrand’s disease); in pregnant, lactating, or breeding bitches; or in animals <6 weeks old.d
Drug Interactions
The manufacturer does not list any specific drug interactions on the package insert; however, the concomitant use of potentially nephrotoxic drugs (e.g., aminoglycoside antibiotics) should be done with caution.d Likewise, because of the possibility of dire GI side effects, the simultaneous use of other antiinflammatory drugs, corticosteroids, and NSAIDs should be avoided.d The concurrent use of other highly protein-bound drugs or drugs metabolized in a similar fashion has not been investigated, thus requiring careful use in such settings.d These medications include anticonvulsant, cardiac, and behavior-modifying drugs.d
Ketoprofen
Ketoprofen is a propionic-acid derivative that is approved in the United States as an intravenous preparation for horses.e It exhibits antiinflammatory, analgesic, antipyretic, and antibradykinin activities. Ketoprofen inhibits the synthesis of prostaglandin through nonselective COX inhibition, although it appears to be relatively COX-1 selective in dogs.9,52 It has been shown in vitro to inhibit lipoxygenase, yet it is questionable whether this inhibition occurs at clinically relevant dosages.53 These properties make ketoprofen a suitable choice for the management of symptoms associated with musculoskeletal inflammation in both acute and chronic settings.54
Commercially available forms of ketoprofen contain a mixture of both the S(+) and R(−) enantiomers, with the S(+) enantiomer providing most of the drug’s antiinflammatory activity.52 The R(−) enantiomer is included in the mixture, because it possesses greater analgesic activity and has minimal ulcerogenic tendencies.55 After intravenous administration, maximum blood levels are reached within 0.83±0.61 hours.56,57 The drug has a bioavailability of 90%±10%, with a short termination half-life in a healthy horse of 0.88 hours.56,57 Ketoprofen is not approved for use in dogs and cats in the United States, but its extralabel use as a postoperative analgesic has been described.58 In Europe and Canada, oral and injectable forms of ketoprofen are approved for use in both dogs and cats.58
Contraindications and Warnings
Gastrointestinal upset (e.g., ulceration, bleeding, vomiting) has occurred with oral administration of ketoprofen.52 Ketoprofen has been associated with decreased platelet aggregation, because it inhibits both COX-1 and COX-2; therefore, the use of ketoprofen in the preoperative period and in animals with hemostatic disorders should be done with caution.59 As a result of urinary excretion, plasma concentrations of ketoprofen may be increased with concurrent renal failure or insufficiency; thus, caution and intensive monitoring is required if ketoprofen is used in these cases.60 In humans, failure to correct ketoprofen dosage for renal dysfunction has resulted in dangerously high serum drug levels.60
Drug Interactions
The use of ketoprofen should be avoided in conjunction with other NSAIDs because of the increased possibility of GI mucosal damage and ulceration.50 Probenecid should not be used with ketoprofen, because it decreases renal excretion and increases plasma concentrations of the drug.50 Ketoprofen is also associated with decreased platelet aggregation and should not be used in combination with anticoagulant drugs, such as warfarin.61
Meloxicam
Meloxicam is in the enolic acid class of NSAIDs and has analgesic, antiinflammatory, and antipyretic properties.30 Meloxicam is COX-2 preferential but not COX-2 specific, which means that at high doses, the specificity of meloxicam for the COX-2 isoenzyme is decreased.30 Like etodolac, meloxicam is well absorbed after oral administration, and food does not appear to affect its absorption.62 Unlike etodolac, meloxicam does not reach maximum blood concentrations until 7 or 8 hours after oral administration.30
Meloxicam undergoes extensive enterohepatic recirculation and hepatic metabolism.62 None of the metabolites of meloxicam have been shown to have pharmacological effects.30 Both unchanged drug and its metabolites are primarily eliminated in the feces. The serum half-life of meloxicam is species specific, averaging 24 hours in the dog and approximately 3 hours in the horse.30
Meloxicam appears to be efficacious in the management of chronic pain associated with osteoarthritis in dogs.63 Doig et al. found that meloxicam significantly reduced the clinical signs of chronic locomotive disorders in the dog.63 Lameness, stiffness, pain on rising, and exercise intolerance all improved in dogs treated with meloxicam.63 Meloxicam is also efficacious in the management of postoperative pain in dogs.64 Although the label stipulates that meloxicam is indicated specifically for the management of pain and inflammation in the dog,f short-term and pulse administration of meloxicam in cats is under investigation.30
Contraindications and Warnings
Hypersensitivity to meloxicam is a contraindication for its use. Gastrointestinal ulceration, hemorrhagic diseases or coagulopathies, and impaired hepatic, renal, or cardiac function are also contraindications.30,62 Caution must be exercised in the administration of meloxicam in animals with hypovolemia or dehydration because of the risk of decreased renal perfusion and nephrotoxicity from inhibition of PGE2.30,62,63 Meloxicam is not recommended in pregnant or lactating animals or in animals <6 weeks of age.f,62
Meloxicam may be associated with GI upsets (e.g., vomiting, diarrhea, anorexia), but such problems occur rarely and are often transient.30 Although meloxicam primarily acts on COX-2, it may inhibit constitutive cyclooxygenase at high doses; thus, adverse clinical signs may become more apparent at higher dosages.30 Specific information regarding the treatment of overdosage of meloxicam has not been reported. In the event of an overdose, symptomatic and supportive care is recommended.30
Drug Interactions
The simultaneous administration of meloxicam and drugs potentially toxic to the GI tract or kidneys (e.g., other NSAIDs, corticosteroids) is not recommended.30,62 Because meloxicam may decrease platelet agglutination, the concurrent use of other anticoagulants (e.g., warfarin [Coumadin], aspirin, heparin) is also not recommended.30,62 Meloxicam is about 97% protein bound, so it may displace other highly protein-bound pharmaceuticals (e.g., warfarin). Meloxicam may also reduce the efficacy of angiotensin-converting enzyme inhibitors.30,62
Deracoxib
Deracoxib is in the coxib class of NSAIDs, which target the COX-2 enzyme. Deracoxib is the only drug in the coxib class approved by the Food and Drug Administration for use in dogs.g At the time of its introduction in the United States, the primary use for deracoxib was the management of postoperative pain and inflammation associated with orthopedic surgery. More recently, the label indications for the use of deracoxib have been expanded to include control of pain and inflammation associated with osteoarthritis.h,i
The coxib class of NSAIDs target inducible cyclooxygenase, but they competitively inhibit COX-1 at higher doses (i.e., >8 mg/kg per day).h Bioavailability is greatest when deracoxib is administered with food. Although postprandial administration is preferable, administration in fasted animals has also resulted in improvement of clinical signs associated with osteoarthritis and postoperative pain.i Metabolism of deracoxib occurs primarily in the liver.h The drug has an elimination half-life of 3 hours for oral dosages of 2.35 mg/kg, although clinical effects may be observed for a longer time period.h Deracoxib is approximately 90% protein bound, so the concurrent use of other highly protein-bound drugs necessitates close monitoring. Deracoxib is excreted predominantly in the feces as both metabolized and unchanged drug. Up to 20% of the drug may be excreted in the urine.h
Contraindications and Warnings
Hypersensitivity to deracoxib is a contraindication for its use. Adverse reactions to deracoxib have been infrequent (only one per 20,000 tablets dispensed).j Of the 1680 reported cases of adverse reactions to deracoxib during its first 18 months of availability in the United States, 38% of affected animals had concurrent diseases, and 28% were also receiving corticosteroids or other NSAIDs.j The most commonly affected organ system was the GI tract (51% of the reported cases).j Renal and hepatic side effects were reported in 22% and 15.2% of the cases, respectively.j
Ongoing GI ulceration, coagulopathies, or impaired hepatic, renal, or cardiac functions necessitate increased supervision of clinical patients. Deracoxib has not been evaluated in pregnant or lactating animals or in dogs <4 months of age. Deracoxib should not be administered to dogs weighing <1.8 kg (4 lbs), and it is not intended for use in any species other than the dog.h
Drug Interactions
The simultaneous use of drugs potentially toxic to the GI tract or kidneys (e.g., other NSAIDs, corticosteroids) should be discouraged.i,j26,27 Because deracoxib is about 90% protein bound, the concurrent use of anticoagulants (i.e., warfarin [Coumadin], aspirin, heparin), anticonvulsants, and cardiac medications must be done with caution, as possible complications have not been fully evaluated.i
Tepoxalin
Tepoxalin is a relatively new NSAID with analgesic, antiinflammatory, and antipyretic properties. Tepoxalin’s mechanism of action is slightly different from other NSAIDs approved for use in animals. While tepoxalin inhibits both COX-1 and COX-2, unlike other NSAIDs it also inhibits lipoxygenase.65 Tepoxalin also inhibits thromboxane, PGE2, PGF2α, and LTB4.65,66 Tepoxalin’s novel properties give it an unusual COX-2:COX-1 ratio of 30.k,43,67 The ratio studies tested COX enzymes that were purified from ram seminal vesicles, so similar results in other species must still be proven.k,43,67 Lipoxygenase-derived LTB4 is a potent chemotactic agent that recruits, activates, and prolongs the actions of neutrophils and other inflammatory cells and upregulates cytokine production.68–70 By reducing the production of LTB4, dual-acting antiinflammatory drugs like tepoxalin offer a novel approach to the preservation of GI mucosal integrity and may differentially suppress prostaglandin synthesis in a variety of tissues.k,3,65
Tepoxalin is supplied as a rapidly disintegrating tablet that completely dissolves within a few seconds in the pet’s mouth.l The parent compound reaches maximum plasma concentrations in approximately 2 hours, but it is then rapidly converted to an active metabolite.l Both the parent compound and the active metabolite inhibit cyclooxygenase, but it is the long plasma half-life of the active metabolite that allows once-daily dosing.l It appears that the active metabolite does not contribute to lipoxygenase inhibition.k Both the parent compound and the metabolite are excreted primarily through the feces (<1% is excreted through the kidney).k Tepoxalin should be administered with food or within 1 to 2 hours of eating.l
Contraindications and Warnings
Hypersensitivity to tepoxalin is a contraindication for its use.l Because tepoxalin has not been evaluated in pregnant or lactating bitches or in dogs <6 months of age, its use in these animals is not recommended.l Animals weighing <3 kg cannot be dosed accurately, so a low body weight is a relative contraindication.l
Tepoxalin has a low occurrence of side effects when given at the recommended dosage.k However, animals should be closely monitored for GI signs, and therapy should be terminated if such signs appear.l Concurrent use of other NSAIDs or corticosteroids should be avoided. The simultaneous administration of other highly protein-bound drugs has not been thoroughly investigated and demands close monitoring.l
Discussion
The volume of ongoing research on NSAIDs and recent discoveries pertaining to this class of drugs in humans can make the selection of a drug for a specific need very difficult. In general, the use of NSAIDs can be grouped into two categories: 1) short-term therapy as an anticoagulant, antipyretic, antiinflammatory, or an analgesic agent; and 2) long-term therapy for the management of chronic osteoarthritis. Both of these treatment categories require the practitioner to weigh the risks and rewards associated with each potential therapeutic agent and to assimilate that information into a comprehensive treatment plan. In evaluating NSAID choices for clinical use, efficacy and safety should be the primary determining factors and priorities. Comprehensive knowledge of the contraindications, precautions, and side effects is very important before prescribing any of these drugs.
Recent data regarding some of the major COX-2 inhibitors used in humans indicate that COX-2 inhibitors may be associated with cardiovascular side effects, such as myocardial infarction and stroke.71 While the specific classes of COX-2 inhibitors implicated in these cardiovascular events are closely related to commercially available veterinary products, no evidence has been provided to date that suggests similar events occur in small animals.
More research into the interrelationship of the COX and lipoxygenase enzymes and their roles in both physiological and pathological settings is needed. By understanding the mechanisms of action of the currently available agents, the likelihood and severity of potential adverse reactions, as well as specific contraindications for each NSAID, veterinarians will be better prepared to formulate individual treatment regimens based on each animal’s needs.
Conclusion
The volume of information and ongoing research on NSAIDs can make the selection of a specific drug to meet a specific need daunting for both veteran and novice practitioners. In general, the use of NSAIDs can be grouped into two large categories: short-term therapy (e.g., temporary anticoagulation, antipyresis, antiinflammation, or analgesia) and long-term therapy (e.g., management of chronic osteoarthritis). Both of these settings require the practitioner to weigh the risks and rewards associated with each potential therapeutic agent and assimilate that information into a comprehensive treatment plan.
EtoGesic package insert 2001; Fort Dodge Animal Health, Fort Dodge, IA 50501
Freedom of Information Summary: New Animal Drug Application 141-108, Etogesic for Dogs (etodolac), 1998.
Freedom of Information Summary: New Animal Drug Application 141-053, Rimadyl (carprofen) Caplets for Dogs, 2001.
Rimadyl package insert 2004; Pfizer Animal Health, Exton, PA 19341
Freedom of Information Summary: New Animal Drug Application 140-269, Ketofen (ketoprofen) for Horses, 1990.
Metacam package insert 2003; Boehringer Ingelheim Vetmedica GmbH, 55216 Ingelheim/Rhein, Germany
Deramaxx clinical and technical review 2003; Novartis Animal Health US Inc., Greensboro, NC 27408
Deramaxx package insert 2002; Novartis Animal Health US Inc., Greensboro, NC 27408
Deramaxx package insert 2004; Novartis Animal Health US Inc., Greensboro, NC 27408
Deramaxx Advisor for the practicing veterinarian. Pharmacovigilance summary and clinical experience since its USA launch 2004; Novartis Animal Health US Inc., Greensboro, NC 27408
Zubrin technical monograph 2003; Schering-Plough Animal Health, Union, NJ 07083-1982
Zubrin package insert 2002; Schering-Plough Animal Health, Union, NJ 07083-1982
Citation: Journal of the American Animal Hospital Association 41, 5; 10.5326/0410298
Schematic depicting the roles of cyclooxygenase (COX)-1, COX-2, and lipoxygenase (LOX) in the liberation of inflammatory mediators via the arachidonic acid cascade.
