Prostaglandin Formation

Eicosanoids, such as PGs and leukotrienes, are 20-carbon chain derivatives of cell membranes. Eicosanoids are potent mediators of inflammation and are particularly important in the later stages.^3,8 These compounds are synthesized when oxygen reacts with the polyunsaturated fatty acids of cell membrane phospholipids (see Figures 29-1 and 29-2). The most important of these fatty acids is AA, an omega-6 fatty acid, which is released into the cell from phospholipids of the damaged cell membranes. Release reflects activation of phospholipase A₂ (dependent on calcium and calmodulin) located in the cell membrane.⁹ Once inside the cell, AA serves as a substrate for enzymes that generate intermediate and ultimately the final eicosanoid end product.^8,10 The formation of lipoxygenases and their subsequent inhibition is discussed under “Miscellaneous Antiinflammtories.” COX PG synthase or prostaglandin H (PGH) synthase, located in all cells except mature red blood cells, add oxygen to AA, generating unstable PG endoperoxides (PGG₂). Subsequent peroxidase reactions convert PGG₂ to PGH₂, the precursor of all PGs and thromboxane. The final PG end product depends on the presence of specific isomerase reductase or synthetase enzymes, some of which may be inducible.^8,9

The direct effects of PGs are mediated through cell membrane–spanning G protein receptors located on target tissues and cells. At least nine subtypes have been identified, corresponding to each of the COX metabolites: DP1-2 (PGD₂), EP1-4 (PGE₂), FP A, B (PGF_2α), IP (PGI₂), and TP α, β (TXA₂) (G&G);¹¹ another four have been characterized for PGE₂, opening the potential for selective drug activity.⁹ In addition to their receptor interactions, PGs also act indirectly by enhancing other mediators such as histamine and bradykinin.

The role of PGs in normal physiology as well as in disease might best be understood by considering them as protective in nature, even those associated with inflammation. Their formation is mediated by one of at least two isoforms of cyclooxygenases (see Figures 29-1 and 29-2), located on different genes in humans.^12-14 COX-1, the “housekeeping” isoform,¹⁴ mediates the formation of constitutive PGs produced by many tissues, including gastrointestinal cells, platelets, endothelials cells, and renal cells. PGs generated from COX-1 are constantly present, providing homeostasis through a variety of normal physiologic effects. These include protection of the gastrointestinal mucosa, hemostasis, and the kidney when subjected to hypotensive insults. COX-2 is the product of an “immediate-early” gene that is rapidly inducible and tightly regulated.¹⁴ Regulation of COX expression is complex, with more sites present on the COX-2 compared with the COX-1 gene. Its expression is tightly restricted (but not absent) under basal conditions, but it is dramatically upregulated in the presence of inflammation or other diseases.⁹ Diseases associated with increases include (in humans) rheumatoid arthritis, seizures, ischemia, and (posttranslational) cancer.⁹ Proinflammatory cytokines such as TNFα and the interleukins stimulate the expression of COX-2 in many cell types, such as synovial cells, endothelial cells, chondrocytes, osteoblasts, and monocytes and macrophages.¹⁴ COX-2 catalyzes the formation of inducible PGs, which are needed only intermittently or under specific situations.^12,13,15,16 A third COX isoform has been suggested, but it appears to be a variant of COX-1. Originally identified in high concentrations in canine cerebral cortex (hence the term used by some investigators, “canine COX-3”),¹⁷ it is inhibited by acetaminophen (and other NSAIDs). Its inhibition may influence central analgesic effects of NSAIDs.^1,2 Differential or selective inhibition of COX-2 clearly offers potential some safety benefits by avoiding loss of homeostatic PGs; however, loss of COX-2 activity is also associated with adversities.¹⁴ It is important to note that COX-2 is ofttimes constitutively expressed: in the kidney and brain it mediates a cytoprotective effect in damaged or inflamed gastrointestinal mucosa.

Cyclooxygenases in health and disease

An appreciation of both efficacy and safety of COX inhibition (e.g., NSAIDs) is facilitated by an understanding of the role of COX in healthy and diseased tissues. COX has been described as the most common target of drug therapy with NSAIDs. In general, inhibition of COX-2 is responsible for efficacy, whereas inhibition of COX-1 is responsible for side effects.⁹ However, strict adherence to this simplistic approach will lead to therapeutic failure and increased morbidity with NSAID use. Although COX-1 does indeed appear to be the predominant constitutive enzyme responsible for housekeeping, both COX-1 and COX-2 are constitutively expressed in many tissues. Further, although COX-2 clearly is more active in the promotion of inflammation, COX-1 does appear to have some role.

Gastrointestinal and Other Healing

Both COX-1 and COX-2 are constitutively expressed in the gastrointestinal tract. However, constitutive expression of COX-1 has a predominant role in the protection of the gastrointestinal tract. COX-1 PGs decrease hydrochloric acid secretion, increase mucosal bicarbonate and mucus production, and increase epithelial cell proliferation and mucosal blood flow (Figure 29-5). The latter effect facilitates delivery of oxygen and nutrients to proliferating cells as well as rapid removal of damaging hydrogen ions that make their way into the mucosa. Drugs that express preferential potency for COX-2 PGs generally are associated with fewer gastrointestinal side effects compared to those targeting both COX isoforms, although the relative protection varies with the drugs. Protection appears to be more important in the presence of high drug concentrations (e.g., high doses).²⁰ COX-2 is critically important to the gastrointestinal tract as well, being important for healing of gastrointestinal damage: COX-2 appears within 1 hour of gastrointestinal damage. Newer coxib PGs will inhibit gastrointestinal healing as has been demonstrated in dogs receiving firocoxib (see the discussion of tepoxalin).²¹ Interestingly, in the pancreas, constitutive COX-2 expression dominates, although the clinical relevance of this is not yet known.²⁰ The impact of NSAIDS on bone healing is an emerging concern. COX influences osteoblast and osteoclast; experimental studies have demonstrated impaired bone healing.^20a Their use in controlling pain and limiting ectopic bone growth must be balanced with the increased risk of impaired fracture healing; conventional NSAIDs might be preferred compared to newer NSAIDs. The impact of NSAID on soft tissue healing (or ligaments) remains to be confirmed; whereas short term use may have minimal negative (and potentially a positive) impact, long term used might be approached cautiously. A recent meta-analysis in humans found no advantage in terms of return to function for coxibs, but recommended caution with long term use.^20b A strong association has been reported between NSAIDs and severe necrotizing soft tissue infections.^20c

Figure 29-5 Among the many protective functions of constitutive prostaglandins is protection of the gastrointestinal mucosa from acid and other mediator-induced damage. Protective mechanisms include production of mucus and bicarbonate and inhibition of hydrogen ion secretion; epithelial turnover, which ensures rapid replacement of damaged cells; and increased mucosal blood flow, which ensures provision of oxygen and nutrients to the rapidly dividing epithelial cells as well as removal of hydrogen ions that are able to pass into the cells.

Cardiovascular Disease

The role of PGs in the cardiovascular system is largely beneficial, and the relationship between COX-1 and COX-2 and their respective PG end products exemplifies the complex “ying–yang” balance that characterizes them (Figure 29-6). Platelets contain thromboxane, a synthase, which catalyzes the formation of thromboxane from AA. Thrombosis reflects platelet aggregation and vasoconstriction. The formation of a thrombus is kept in check by the presence of prostacyclin synthase in vascular endothelial cells. This enzyme catalyzes metabolism of AA to prostacyclin (PGI2), a vasodilatory and platelet-inhibiting PG end product. However, whereas thromboxane A2 (TXA2) is associated with COX-2, prostacyclin synthase co-localizes with COX-1. Thus, whereas drugs that target both COX isoforms will potentially allow the balance to be maintained, drugs that preferentially target only one isoform risk disruption of the balance. Such may be the case with COX-2 selective NSAIDs. Their preferential inhibition of COX-2 may allow thrombus formation to go unchecked, increasing the risk of thromboembolic disorders. Indeed, in a meta-analysis of human clinical trials, two coxib drugs (rofecoxib and valdecoxib) were associated with an increased risk of stroke (see “Adverse Events”).^20d

Figure 29-6 The role of constitutive prostaglandin products in hemostasis exemplifies the “ying-yang” relationship that often characterizes their action. Platelet activation in response to the damage is accompanied by the release of arachidonic acid, which is catalyzed by thromboxane synthetase, present in platelets, to thromboxane. Thromboxane causes platelet aggregation and local vasoconstriction. Excessive hemostasis is kept in check, however, by the simultaneous release of arachidonic acid from the damaged endothelial cell surface. Prostacyclin synthetase, located in the endothelial cells, results in the formation of prostacyclin, which is vasodilatory and inhibits platelet aggregation. cAMP, Cyclic adenosine monophosphate.

Kidney

In the kidney both COX-1 and -2 are constitutively expressed. Both are formed in the macula densa of humans and animals, but COX-2 may have a more important role than COX-1 (Figure 29-7). In animals, inhibition of COX-2 causes sodium and potassium retention in salt-depleted, but not normal, animals. However, in humans COX-2 appears to influence renal vasculature and podocytes. The role of COX in the kidney requires further elucidation before safety can be assumed for any NSAID; sparing COX-1 and targeting COX-2 can be expected to alter renal function. For example, kidneys do not develop in the embryos of COX-2–null knockout mice.²² The role of COX differs among tissues and species; their impact on adverse reactions are addressed under “Adverse Reactions.”⁹

Figure 29-7 Both constitutive and inducible prostaglandins are important to renal blood flow, with the specific effect of each product varying among species. Renal prostaglandins ensure that intramedullary renal blood flow and urine formation will continue in the presence of decreased renal perfusion. Sites of action are noted by numbers and include shunting of blood from the cortices to the medullary intersitium, stimulation of natriuriesis, and inhibition of antidiuretic hormone. The nephrotoxicity of selected drugs reflects inhibition of renal prostaglandins.

Cycloloxygenase and nonsteroidal antiinflammatory drugs

NSAIDs (Table 29-2) act to block PG synthesis by binding to and inhibiting cyclooxygenase (see Figures 29-1 and 29-2).⁸ This action is both dose and drug dependent. The planar form that characterizes these drugs is thought to facilitate their binding to COX.^6,25 Several investigators have shown that some drugs (e.g., phenylbutazone and flunixin meglumine) also reduce later steps of the formation of PGE₂ in inflammatory exudate at therapeutic doses.²⁶ However, both the major therapeutic and toxic effects of NSAIDs have been correlated extensively with their ability to inhibit PG synthesis, with anti-inflammatory potency related to potency of impaired PG synthesis.⁸

Table 29-2 Dosages of Nonsteroidal Antiinflammatory Drugs in Cats and Dogs

The differential effect of NSAIDs on the isoforms of COX presumably contribute to clinical differences in efficacy and safety, .^17,27 Whereas as a class, NSAIDs appear to inhibit both COX-1 and COX-2, the ratio of the concentration of a NSAID necessary to inhibit the same level of COX-1 vesrus COX-2 activity (e.g., inhibition of 50% or 80% activivity [IC5₀ or IC₈₀]) compares the potency each drug toward each isoform, and as such, provides a basis for screening predicted relative safety and efficacy of each. Thus, a COX-1 to COX-2 ratio greater than 1 (or a COX-2 to COX-1 ratio of less than 1) indicates greater potency for COX-2 which is desirable in that formation of inflammatory PGS should be inhibited preferentially to the housekeeping PGs.^12,13,15,16 Inhibition of platelet activity is commonly used to measure in vitro COX-1 inhibition whereas inhibition of PGs released from macrophages stimulated with endotoxin is used to measure COX-2. A number of drugs associated with in vitro COX-2 selectivity in humans, including rofecoxib (Vioxx) and celecoxib (Celebrex); others include etodolac, meloxicam, and nimesulide; the newest drugs are valdecoxib, etoricoxib, and (soon to be approved) lumiracoxib.⁹ Drugs approved for use in animals include carprofen (the first) followed by etogesic; deracoxib; meloxicam; and, most recently, firocoxib.

Although the gene for COX-1 is about 3 times as large as that for COX-2, the two COX proteins, which are membrane bound, share about 60% homology.⁹ Differences in NSAID selectivity for these two enzymes reflects smaller amino acids at two positions in COX-2 compared with larger amino acids at the same site in COX-1. The result is a larger and more flexible “pocket” into which the newer drugs insert and inhibit the COX-2 isoform.⁹ For example, ”coxib” drugs contain a sulfonamide group that interacts through hydrogen bonding to arginine of COX-2 but not histidine in the same position in COX-1.²⁸ Despite the usefulness of the COX-1:COX-2 ratio in screening drugs for safety or efficacy, its applicability to clinical use is questionable. Further, comparing results among studies is difficult. For example, whereas some studies focus on the IC_50, others determine the IC₈₀, the latter probably being more clinically relevant. Assay methods contribute to variability in ratios among investigators for the same drug in the same species (Table 29-3). In vitro assasys based on cell culture or recombinant enzymes are easier to perform, but it is the ex vivo whole blood assays (as opposed to in vitro cell culture assays) that generally are recognized as the most representative of the clinical patient.¹ However, even whole blood assays do not take into account different distribution patterns to different tissues.^18,22 Extrapolation among species should be avoided.²⁹ For example, wherease the COX-1 to COX-2 ratio of etodolac is much better than that for carprofen in humans,^20,30 the opposite is true in dogs. Indeed, Wilson and coworkers³¹ have demonstrated that, wherease critical residues in the active sites of canine COXs are identical with human homologs, amino acids differ (up to 54) at in active sites and may contribute to differences in activity that preclude extrapolation among species (see Table 29-3). Further complicating extrapolation among and within species is the fact that NSAIDs generally exist and are largely marketed as enantiomers (see Chapter 1), each with a possible different ratios. For example, Ricketts and coworkers³² found the COX-1:COX-2 ratio of carprofen to be 129 for the racemic mixture but 181 for the S isomer and only 4.19 for the R isomer. Little information is available regarding COX selectivity in cats.^33,34 Much of the information that is available is based on manufacturer-sponsored studies and as such might potentially reflect reporting bias. For example, in Table 29-3, drugs that generally performed best in each study tended to be the drug manufactured by the sponsor of the study. As such, COX ratios might be considered a screening procedure^1,2

Table 29-3 COX-1 to COX-2 Ratios for Selected Nonsteroidal Antiinflammatory Drugs in the Dog by Different Investigators

Pharmacologic Effects

The pharmacologic effects of this class of drugs include analgesia, antipyresis, and control of inflammation. Antithrombosis also occurs, but this effect is variable, being the greatest for aspirin and the least to absent for newer COX-2 selective drugs. The effects are dose and drug dependent and include antithrombosis (when present), which occurs at the lowest concentrations (relatively lower for aspirin compared to all others); followed by antipyresis, analgesia and antiinflammation, with the latter occurring at the highest concentrations, although an exception appears to occur again for aspirin.^10,43d Studies that compared efficacy and safety traditional or newer NSAIDs are generally are based on in vitro or ex vivo methods, with clinical trials limited. Yet, differences should be anticipated even among the newer NSAIDs. The mechanisms by which NSAIDs inhibit (interact with) COX are responsible, in part, for the variable antiinflammatory effects that characterize these drugs. Although several NSAIDs are characterized by a short plasma elimination half-life, the clinical response may last for over 24 hours after a single dose or up to 72 hours after multiple doses. These differential durations reflect, in part, drug-receptor interactions,with irreversible binding to COX most likely contribute to a longer biologic response.⁴⁴ Lees and co-workers have reviewed the relationship of NSAID effect and dose, emphasizing the advantages of PK-PD modeling as a basis of dose design.^44a Inhibition of COX-1 has been described as simple competitive inhibition, whereas that for COX-2 has been described as a slowly reversible, contributing to a longer biologic versus plasma half-life.⁴⁵ Aspirin binds reversibly to the COX activity site on PGH synthase and then irreversibly inactivates the enzyme by acetylating a serine residue.¹⁰ Both thromboxane and prostacycline synthase are impacted. However, platelets cannot produce additional thromboxane synthase; as such, platelet activity depends on new platelet production in the absence of aspirin. In contrast, endothelial cells are able to synthesize more prostacyclin synthetase and are less susceptible to the inhibitory effects of low dose aspirin.¹⁰ In contrast to irreversible binders of COX, ibuprofen binds reversibly with COX and thus competes with AA for binding. In laboratory animals and humans, a relative potency (not to be confused with efficacy) has been established for selected conventional NSAIDs and COX: meclofenamic acid >indomethacin >naproxen >phenylbutazone >aspirin.⁴⁴ However, differential potency for COX-1 versus COX-2 varies among the NSAIDs and their enantiomers. In addition to drug-receptor interaction, prolonged elimination of NSAIDs from inflammatory exudate compared with plasma may also result in differential effects among the drugs and species.^37,44

Along with inhibition of PGs, disruption of cellular signaling is responsible for all three pharmacologic effects (antiypresis, analgesia, anti-inflammation) that characterize all NSAIDs.¹⁰ The antipyretic effect of NSAIDs may or may not be of benefit. Indeed, in human medicine little scientific support exists for the use of antipyretics for relief of discomfort or reduction of morbidity and mortality associated with fever.⁴⁷ Fever may have a beneficial effect on the outcome of bacterial or viral infections and often inversely correlates with the severity of lesions or the time to resolution. Thus the antipyretic effects of NSAID may be of most benefit when increased metabolism induced by fever might prove detrimental, such as with septicemia.⁴⁷ Central analgesic effects have been suggested for some but not all NSAIDs because NSAIDs can provide analgesia at very low intrathecal doses.^15,16,46

The impact of COX on disease has led to a number of new applications for NSAIDs. The antiendotoxic effect of selected NSAIDs has been known (see the discussion of flunixin), but newer mechanisms are being examined. For example, several NSAIDs (carprofen, flunixin meglumine, and phenylbutazone) may specifically inhibit activation of the proinflammatory transcription factor nuclear factor kappa B (NF-κB) and on lipopolysaccharide (LPS) induction of iNOS. Using a mouse macrophages line, carprofen and flunixin, but not phenylbutazone, inhibited iNOS, whereas carprofen and, to a lesser degree, flunixin, inhibited NF-kappaB activation.³⁵

Because NSAIDs are commonly first-choice treatments for arthritis, a focus on the effects of NSAIDs on cartilage is warranted. NSAIDs have been shown to inhibit proteoglycan synthesis in vitro, and for the salicylates this is supported by in vivo studies.⁴⁸ This effect has been attributed to inhibition of uridine diphosphate glucose dehydrogenase, an enzyme important in proteoglycan synthesis.⁴⁸ Hyaluronic acid synthesis, also dependent on this enzyme, does not appear to be as affected. The clinical effects of NSAIDs on cartilage are controversial. Some NSAIDs may, in fact, favorably modify the metabolism of proteoglycans, collagen, and matrix and may decrease the release of proteases or toxic oxygen metabolites.⁴⁸ This may reflect, in part, control of inflammation. Thus, whereas several NSAIDs have documented adverse effects on normal cartilage, ranging from decreased proteoglycan synthesis (e.g., aspirin) to chondrocyte death (phenylbutazone), others (e.g., naproxen, piroxicam, ketoprofen, and possibly carprofen) are recognized for their chondroprotective effects. Dual inhibitors have been noted for their potential efficacy to slow the progression of arthritis.^48b

The use of NSAIDs in the control of acute pain is evolving. Preemptive use (just before and immediately after surgery) has been demonstrated in humans to be more effective than either placebo or control,¹⁷ and similar findings have been reported in the clinical use of COX-1–sparing drugs in animals. Drugs that target COX-2 (NSAIDs) offer a morphine-sparing effect for control of postoperative pain.¹⁷ Their use in multimodal analgesia is increasing.

NSAIDs are currently being investigated for their potential antitumor effects. Knapp and coworkers⁵⁰ found piroxicam to be clinically useful in reducing tumor size and increasing survival time in dogs with transitional cell tumors of the urinary bladder. The result does not appear to reflect direct cytotoxic effects.^49-51 NSAIDs may be beneficial when combined with other anticancer drugs.⁵² The effects of drugs inhibiting COX-2 cancerogenesis may be dose dependent: At least for aspirin, the maximum anticancer effect occurs at a dose less than that associated with control of inflammation but similar to that associated with antiplatelet effects.⁹ Mechanisms other than COX inhibition contribute to NSAID antitumor effects.^51a In addition to the inhibition of cancer growth, the use of COX-1–sparing drugs may improve gastrointestinal tolerance of anticancer drugs.

Risk factors for NSAID-induced gastrointestinal adverse events

Several risk factors for NSAID-induced gastrointestinal adverse events identified in humans are applicable to animals. No chemical characteristic predicts the likelihood of gastrointestinal toxicity by a particular conventional NSAID.^70,72 Drugs that undergo enterohepatic circulation (e.g., naproxen, carprofen, etodolac) may be associated with a greater incidence of gastrointestinal upset. Other risk factors include advanced age (altered disposition coupled with decreased ability to protect damaged mucosa),⁷⁷ concurrent use of glucocorticoids (increasing the risk 4.4-fold in humans) or other NSAIDs (the exception might be low-dose aspirin, as discussed later), or anticoagulants. Comorbidity (renal, cardiovascular, or liver disase) is also a risk factor.⁷³

The combination of steroids and NSAIDs causes worse lesions than either drug alone, as has been demonstrated for flunixin meglumine or dexamethasone.^74,78,79 Further, the FDA adverse drug events site indicates that the risk of gastrointestinal toxicity is greater when drugs are given with glucocorticoids. In a restrospective study of gastrointestinal perforation associated with deracoxib, a risk factor was combination with glucocorticoids (or other NSAIDs) within the past 24 hours.⁸⁰ Other NSAIDs appear to shift use of AA from the COX pathway to the production of cysteinyl LTs and LTB4, eicosonoids that promote leukocyte migration, break down the mucosal barrier, and stimulate gastric acid secretion. Inhibition of COX-2 may preclude angiogenesis critical to the healing ulcer.⁸¹ Persons with previous history of gastric ulcer disease also are predisposed to NSAID-induced gastrointestinal adverse drug events. Although peptic ulcer disease is unusual in animals, prudence dictates that evidence of any gastrointestinal disease associated with mucosal damage (e.g., inflammatory bowel disease) that might require COX-2–mediated healing be considered a potential risk factor.

Dose-dependent toxicity has been demonstrated during the approval process essentially for all NSAIDs as is indicated by product package inserts (Table 29-5). The single most common cause of NSAID-induced toxicity found by a review of NSAID-induced adverse drug event reports by the FDA is overdosing, in particular failure to adhere to the recommended dosing regimen. Overdosing was associated with an increased risk of NSAID-induced gastrointestinal perforation in dogs.⁸⁰ Drugs for which low-concentration preparations are not available increases the risk of toxicity because of inaccurate dosing. Use of compounded preparations (for which oral bioavailability is not known) should be implemented with extreme cautions; increasing bioavailability will result in a proportional increase in drug concentrations. The risk for overdosage is greater for selected drugs for which higher doses may result in zero-order elimination (e.g., deracoxib, phenylbutazone). For such drugs half-life is no longer germane, and the risk of drug accumulation dramatically increases.

Table 29-5 Safety Data for Selected NSAIDs in Dogs and Cat Based on Target Safety Studies and Clinical Trial Field Studies

The relationship between dose and risk of toxicity remains complex, even for NSAIDs, as is exemplified by aspirin. At low doses (concentrations), aspirin blocks COX activity and thus shunts AA into the lipoxygenase pathway. Although gastrotoxic LTs are produced (cysteinyl LTs and LTB4), aspirin also simultaneously triggers lipoxin (aspirin-triggered lipoxin [ATL]) formed by lipoxygenase-15. Lipoxin is antiinflammatory and thus inhibits the gastrotoxic leukocyte recruitment and activation caused by cysteinyl LTs, as well as mediates the antiadhesive platelet effects of aspirin. As such, low-dose aspirin tends to be both cardioprotective as well as safe to the gastrointestinal tract. However, at higher doses production of LTs is sufficient that the protective effects of lipoxin are masked and gastrotoxicity emerges. Interestingly, COX-1–sparing (COX-2 preferential drugs) inhibit the formation of lipoxin, contributing to the toxicity of the newer drugs when combined with low-dose aspirin.⁸¹ Theoretically, whereas COX-inhibiting drugs should not be combined with low-dose aspirin, dual-acting NSAIDs, which do not target lipoxygenase-15 (see the discussion of dual-acting NSAIDs), should not inhibit lipoxin and thus should maintain the low-dose aspirin gastroprotective and cardioprotective effects.⁸¹

In general, conventional NSAIDs are associated with a greater risk of gastrointestinal adverse drug events in humans, but exceptions may occur. For example, in humans (but not dogs) ibuprofen, which is essentially equivalent in its COX-1 versus -2 selectivity, is ranked as low risk, along with the COX-1–sparing drugs celecoxib, rofecoxib, meloxicam, and etodolac.⁷³ Comparison in dogs of gastrointestinal safety among newer NSAIDs, including both COX-1–sparing drugs and dual-acting NSAIDs, might be based on toxicity data generated during the approval process and available on package inserts. This latter source includes both targeted safety studies (the dose is multiplied by 3, 5, or 10) and field studies (clinical trials at recommended doses under conditions of anticipated use) (see Table 29-5).

Comparison of clinical safety among NSAIDs ideally should reflect nonmanufacturer-sponsored, well-designed clinical trials involving a sufficient number of animals such that the power is sufficient to detect a significant difference. Placebo controls are imperative; positive responses have been reported in 40% or more of placebo-treated animals.⁸² However, such studies in veterinary medicine are few and far between. Data that do exist thus far support the safety of the newer drugs compared with conventional NSAIDs. For example, using a placebo-controlled, parallel, randomly assigned design in dogs (n = 6/group), Reimer and coworkers⁸³ found that buffered aspirin caused endoscopic gastric lesions within 5 days of starting therapy compared with no or minimal lesions in animals treated with carprofen or etodolac (sample size may have limited the ability to discern a difference between the two groups); all drugs were administered at mid-recommended doses. Endoscopic lesions followed the same relative pattern among drugs throughout the 28-day study period, indicating that aspirin is more commonly associated with lesions in the canine gastrointestinal tract compared with the COX-1–sparing drugs. A separate study found no differences in gastrointestinal lesions in animals receiving ketoprofen (nonselective), carprofen, meloxicam, or placebo. However, the power of this latter study to detect a significant difference was not reported.

Pharmacologic prevention and treatment

Future pharmaceutical manipulations designed to deliver NSAIDs by alternative routes may decrease risk of gastrointestinal adverse drug effects, although their application to veterinary patients should not necessarily be assumed. For example, formation of nitroso derivatives of conventional NSAIDs may improve the safety margin of these drugs as a result of in vivo release of NO that provides gastroprotection while improving antiinflammatory and analgesic potency.² However, NO also has been associated with the pathogenesis of osteoarthritis, thus exemplifying the continuously complicated nature of designing safe NSAIDs (see later discussion).²² In contrast to current drugs that only slowly dissociate with COX-1, newer NSAIDs appear to be weak and rapidly reversible binders of COX-1, thus enhancing safety.^17,45

Topical (including transdermal) NSAID administration is appealing because it avoids direct contact between the drug and target tissue. Indeed, a meta-analysis of clinical trials comparing topical NSAIDs to placebos and oral NSAIDs in humans found this route to be effective, with no difference in response compared with oral. Topical administration was safe, although not necessarily safer than oral. Of the NSAIDs reviewed, ketoprofen was described as the best.⁸⁴ Thus far, topical NSAID administration has not proved to be a vital means of avoiding gastrointestinal adverse drug events in small animals, primarily because of failed drug delivery. Because the amount of drug delivered cannot be predicted, administration of NSAID in novel drug delivery systems offered by compounding pharmacists is not recommended unless the amount of drug delivered by that system has been scientifically demonstrated, as would occur for an approved drug. Enteric coatings, combination drugs (e.g., with gastroprotectants), and other approaches may be of some benefit for some drugs (e.g., aspirin) and, if currently available, are discussed with the individual drugs.

Both the prevention and treatment for gastrointestinal toxicity focus on, in order of priority, control of gastric acid secretion, replacement of the missing PGs, and (for treatment) protection of the damaged mucosa.^64,85 The two major categories included antisecretory drugs and the PG analog misoprostol; cytoprotectants, such as sucralfate, also play a role in treatment.

Among the antisecretory drugs, proton pump inhibitors (PPIs) generally have proved more effective than H₂ receptor blockers for prevention and treatment of NSAID-induced gastrointestinal adverse drug events. An exception has been demonstrated in humans for famotidine, but only when it is administered at higher than recommended doses (40 mg twice rather than once daily).⁷³ Boulay and coworkers⁸⁶ demonstrated that cimetidine did not protect the gastric mucosa from developing lesions in dogs receiving nonbuffered aspirin (35 mg/kg every 8 hours). PPIs appeared to be more effective, as well as better tolerated, compared with misoprostol. In one human study, close to 30% of persons reciving misoprostol could not tolerate the full dose.⁷⁶ Omeprazole generally is the PPI of choice, although lansoprazole may also be a reasonable choice. Although lansoprazole was not found to be superior to misoprostol for prevention of gastrointestinal adverse drug events in humans, improved compliance and better tolerance made it the preferred PPI drug in humans. However, the use of PPI will not prevent ulcers in all patients, as has been demonstrated in humans. Symptoms of GI side effects still occur in 20% of human patients receiving omeprazole.⁷³ Although routine use of PPI in nonrisk animals receiving NSAIDs is not indicated, strong consideration should be given to their use in at-risk animals. As a class, the PPIs are inhibitors of drug-metabolizing enzymes, and care should be taken to review drug interactions before their use. Among them, esomeprazole may be the least likely to impact metabolizing enzymes.^86a However, PPI also have been shown to induce selected CYP45O enzymes (P45OIA1 and A2) but this impact appears to be most clinically relevant to (human) poor metabolizers that are deficient in enzymes.^86b

Misoprostol is a synthetic PPGE analog that both prevents and helps heal gastrointestinal ulceration caused by NSAIDs.⁸⁷ The efficacy of misoprostol has been well established in human patients suffering from NSAID-induced ulceration,⁷¹ and studies support similar benefits in dogs.^88,89 Combination NSAID–misoprostol products have been approved for use by human patients,⁹⁰ supporting its their combined use. Interestingly, misoprostol, when combined with an NSAID, also appears to enhance the antiinflammatory effect of the NSAID.⁹⁰ Indeed, misoprostol inhibits IL-1, TNF, and thromboxane release from macrophages, and it is the most potent inhibitor of histamine release from human mast cells.⁹⁰ Misoprostol has potentiated the antiinflammatory effect of a variety of compounds in animalsand appears to have analgesic effects, although at high concentrations, acting synergistically with other NSAIDs.⁹⁰ Finally, misoprostol may be more effective in the presence of agents that decrease gastric acid secretion.⁶⁴

Gastroprotective drugs include sucralfate and potentially glucosamine–chondroitin products (Figure 29-8). The benefits of sucralfate in the treatment of NSAID-induced adverse drug events include binding to and thus protecting damaged mucosa, as well as increasing PG synthesis, angiogenesis, and sulfhydryl (oxygen radical scavenger) production at the site of damage. Despite the fact that sucralfate binds only to damaged mucosa, it nonetheless consistently performs better than placebo in the prevention of gastric or duodenal ulcers in human patients receiving NSAIDs. Sucralfate is minimally effective than antisecretory drugs in preventing stress ulcers (e.g., critical care patients).^90a The combined use of NSAIDs and disease-modifying agents (glucosamine and chondroitin sulfates) for treatment of osteoarthritis is discussed later. An added advantage of their combined use is the potential gastroprotection that might be realized because of enhanced mucopolysaccharide production.⁹¹ Interestingly, metronidazole has been ascribed a protective effect on the gastrointestinal tract when combined with NSAIDs, presumably through removal of the microbial impact on neutrophil chemoattractant.⁹²

Figure 29-8 A gross (top) and endoscopic view of two gastric ulcers in dogs treated with aspirin and glucocorticoids. The bottom ulcer responded to treatment with misoprostol, sucralfate, and ranitidine.

The Canadian Agency for Drugs and Technologies in Health (CADTH) sponsored an in-depth analysis of the literature in an attempt to identify the most cost-effective gastroprotective strategies in persons receiving NSAIDs.⁹³ In their report, based on Monte-Carlo modeling, investigators considered patients receiving a nonselective NSAID (diclofenac) alone, a COX-2 preferentnial NSAID alone (celexocib); or either group of the NSAIDS with misoprostol, an H₂ receptor blocker (ranitidine), or a proton pump inhibitor (omeprazole). In their 2007 report, they found that no prophylaxis and treatment with a traditional NSAID; but no gastroprotection was least costly but least effective in avoiding adverse events. Of the combinations, PPI consistently was more effective than no prophylaxis; further, the most cost-effective strategy was the combination of nonselective NSAIDs with PPIs. Combination of nonselective NSAIDs with H₂ receptor antagonists also reduced the risk of gastrointestinal complications, but at a higher cost (25%). Use of Cox-2 selective drugs or combination with misoprotol were effective (but more costly) alternatives, although combination with misoprostol was associated with increased adversity because of its PG effects. The CADTH investigators further observed the need for a large, prospective, multicentered clinical outcome study that directly compares the efficacy of PPIs with H₂ receptor antagonists to prevent NSAID-associated gastrointestinal adversities.

The use of 5-lipoxygenase inhibitors for prevention of NSAIDs gastrointestinal toxicity might be considered. Lis facilitate ulcer formation by virtue of their effect on platelets and blood vessels; these effects and others also might be inhibited by LT receptor antagonists (see later discussion). Among the approaches in reducing gastrointestinal toxicity associated with NSAIDs is the development of NO-NSAIDs.⁶⁹ NO has been recognized as an important gastroprotectant. Its mechanism appears, in part, to reflect inhibition of neutrophil adherence to vascular endothelium, which is necessary for mucosal damage to occur. Whereas adverse reactions are likely to preclude use of drugs that promote NO release systemically, NSAIDs that facilitate local release of NO (COX-inhibiting NO donors; NO-NSAIDs) are currently being developed. The drugs contain a NO-releasing moiety; their continuing development has been reviewed.⁶⁹ For example, the addition of the moiety to naproxen has yielded naproxcinod. The gastric mucosa also is protected by the formation of hydrogen sulfide (H₂S) when produced in appropriate quantities. Accordingly, NSAIDs are being designed with a moiety that allows local, limited release of H₂S. In either case (NO- or H₂S-releasing moiety), the antiinflammatory potency of the drug may also be improved as gastric adversity is decreased.

Liver disease should be an anticipated sequela of long-term use of any drug extensively concentrated or metabolized by the liver, including NSAIDs (see Chapter 4).⁹⁴ All NSAIDs approved for use in dogs have been associated with increased liver enzymes; most have been reported scientifically or anecdotally to cause hepatitis. Although their occurrence is discussed with individual NSAIDs, hepatic function tests (e.g., serum bile acids, albumin, urea nitrogen) should be implemented throughout drug exposure in patients at risk (discussed previously). The use of hepatoprotectant drugs (e.g., N-acetylcysteine, S-adenosylmethionine [SAMe]) should be considered for both prevention and treatment.

Clinical signs indicative of gastrointestinal ulceration may be exacerbated by an increased risk of bleeding induced by NSAIDs. In addition to their antiplatelet effects, selected NSAIDs (e.g., phenylbutazone) have also been associated with bone marrow dyscrasias.^95-98 Gastrointestinal bleeding is probably the most common sign of bleeding dyscrasias, in part because of the ulcerogenic properties of these drugs. Epistaxis has also been reported. Because prostacyclin is mediated largely by COX-2, use of COX-2–selective drugs may increase the risk of thrombosis.⁹⁹

Aspirin: The Prototypic Nonsteroidal Antiinflammatory Drug

The discovery of the mechanisms of aspirin and its elucidation of COX enzyme isoforms was recently reviewed.^122a

Flunixin Meglumine

Ibuprofen

Ibuprofen is a propionic acid derivative that has been used in dogs. Ibuprofen may be less effective as an analgesic than aspirin, perhaps on account of differences in binding of COX (reversible for ibuprofen and irreversible for aspirin). Ibuprofen remains a popular and effective antiinflammatory drug in humans. The disposition of ibuprofen has been studied in dogs (see Table 29-4). Pharmacokinetics are similar at doses of 5 and 10 mg/kg.¹⁴⁸ A dose of 12 to 15 mg/kg is, however, necessary to achieve therapeutic concentrations, as reported in humans.¹⁴⁸ After repetitive administration of this dose, plasma drug concentrations decrease despite no change in drug half-life.¹⁴⁸

In humans ibuprofen is associated with a low incidence of gastrointestinal side effects and has been compared favorably with even the newer COX-2–selective drugs.⁷³ This may lead clients to assume the same is true for dogs or cats. However, ibuprofen is among the least safe NSAIDs in dogs. Vomiting commonly occurs after several (2 to 6) days of ibuprofen therapy in dogs with either the gelatin- or enteric-coated capsules.¹⁴⁸ Gastrointestinal inflammation and gastric erosions have been documented after administration of 8 mg/kg daily despite the lack of clinical signs of toxicity.^148,149 Death associated with gastrointestinal hemorrhage occurred in one dog given 3 mg/kg every other day for 6 weeks.¹⁴⁹ These effects occur despite a short half-life for ibuprofen in dogs (less than 5 hours). The COX-1 to COX-2 ratio apparently has not been determined for ibuprofen in dogs. Because gastric lesions occur at doses less than those necessary to achieve therapeutic concentrations, ibuprofen is not recommended for use in dogs.

Ketoprofen

Ketorolac

Ketorolac is an NSAID approved for use in human patients. In contrast to many NSAIDs, ketorolac is only moderately effective as an antiinflammatory.¹⁶⁰ It is a potent analgesic, however, that has been described as equivalent to morphine. As such, it has been used as a perioperative analgesic in dogs.¹⁶¹ Ketorolac appears to be superior to butorphanol and equal to flunixin meglumine for control of postoperative pain. The disposition of ketoralac is quite variable in in dogs (see Table 29-4) after single intravenous or oral dosing (0.34 mg/kg), although investigators indicate that the disposition was simlar to humans.¹⁶² In humans ketorolac causes gastrointestinal upset, and similar side effects occur in dogs. In one study 1 of 21 dogs developed gastrointestinal ulceration after a single dose.⁶⁶ Therefore recommendations are to limit use to one to two treatments, or 3 days. Other side effects reported in human patients include dizziness, headache, nausea, and pain at the site of injection.¹⁶⁰ Caution should be taken particularly in the perioperative patient, which is more likely to be dependent on renal PGs during the surgical procedure.

Meclofenamic Acid

Meclofenamate is an anthranilic NSAID available as a palatable granular preparation intended to be mixed with food for large animals and as a tablet. It is approved for use in dogs in the United States. Among the NSAIDs, it is noted for its slow onset of action. The package insert associated with the label of this drug describes dogs as being exquisitely sensitive to the gastrointestinal ulcerogenic effects of these drugs. Meclofenamic acid appears to have no clear advantage to other drugs for treatment of osteoarthritis in dogs and may be more likely to cause gastrointestinal upset.

Naproxen

Naproxen is approved for use in humans and is available in over the counter preparations. Although it contains a chiral carbon, it is sold as the pure S isomer. Its disposition has been studied in dogs and, notably, it varies from that in humans. Compared with 12 to 15 hours in humans and 5 hours in horses, the elimination half-life of naproxen after intravenous administration in dogs ranges from 45 to 92 hours.¹⁶³ Peak concentrations in dogs after oral administration of 5 mg/kg were 40 to 50 μg/mL. Tissue concentrations paralleled plasma concentrations, with a peak of 20 to 30 μg/mL; concentrations declined over a period of 200 hours.¹⁶⁴ Extensive enterohepatic circulation has been credited as the cause for prolonged elimination in dogs. Because of its long half-life, naproxen need be given only once daily to every other day. Although a loading dose has been recommended, the gastrointestinal toxicity of this drug in dogs suggests that a loading dose be avoided to minimize the risk of toxicity.

The dog has been described as the animal most sensitive to naproxen.¹⁶³ Its use in dogs does not seem prudent. Gastrointestinal toxicity occurs at doses of 5 mg/kg daily.¹⁶⁵ Toxicity appears most likely when plasma drug concentrations exceed 50 μg/mL. If this NSAID must be used in dogs, doses initially should be low (1 to 2 mg/kg) and subsequently titrated to the animal’s need. Animals should be watched closely for evidence of gastrointestinal upset. Bleeding dyscrasias have also been reported in dogs receiving large doses of naproxen.^163,165,166

Naproxen has been cited for a positive protective effect on articular cartilage. In a canine experimental model of osteoarthritis, naproxen decreased the loss of proteoglycans and suppressed metalloproteinase activity.¹⁶⁷

Phenylbutazone

Phenylbutazone is a weakly acidic, lipophilic NSAID approved for use in dogs. Inhibition of the AA cascade by phenylbutazone occurs after conversion to reactive intermediates at the level of PGH synthase and prostacyclin synthase. Prostanoid-dependent swelling, edema, erythema, and associated pain are reduced by phenylbutazone.³⁷ Phenylbutazone has been associated with some attenuation of some clinical signs associated with endotoxic shock in experimental models.^142,144

Bioavailability after intramuscular administration of phenylbutazone is less than that after oral administration in most species studied because of precipitation in the neutral pH of muscle.^37,168 Phenylbutazone is metabolized by the liver, with less than 2% of the drug being excreted as a parent compound in the urine in some species. Its major metabolites are oxyphenylbutazone, which is less active than phenylbutazone, and inactive γ-hydroxyphenylbutazone.^37,169,170 Dose-dependent zero-order kinetics has been reported in dogs.¹²⁷ Reported adverse reactions caused by phenylbutazone include bleeding dyscrasias, hepatopathy, and nephropathy (primarily in horses).^{37,96,171,172} Phenylbutazone has chondrodestructive effects.^173,174

Piroxicam

Piroxicam is an oxicam NSAID approved for humans that has been used to treat osteoarthritis in dogs. More recently, it has received attention for its ability to reduce the size of tumors (transitional cell tumors and others) in dogs.^49,50-52 Piroxicam may interact by an additive or synergistic action with anticancer drugs to cause tumor cell death. Piroxicam is a potent antiinflammatory in musculoskeletal conditions.The disposition of piroxicam has been studied in both the dog¹⁷⁷ and cat.¹⁷⁸ Notably, the half-life of the drug is much shorter in cats (12 hours) compared with dogs (40 to 50 hours). Although the LD₅₀ of piroxicam is greater than 700 mg/kg in dogs, gastric lesions and renal papillary necrosis have occurred in dogs receiving 0.3 to 1 mg/kg daily.^49,177 The ratio of COX-2 to COX-1 suggests that gastrointestinal toxicity occurs. Little evidence of toxicity (gastrointestinal or bleeding), however, was noted after administration of 0.3 mg/kg every other day.^49,177 Extrapolation of human use to dogs should be done cautiously because of possible differences in volume of distribution, therapeutic concentrations, or safety margin.

Carprofen

Deracoxib

Deracoxib is approved for use as an oral chewable preparation in dogs. As a coxib, deracoxib would be expected to be COX-1 sparing, which appears to be true on the basis of studies using cloned canine COX enzymes (see Table 29-3). However, specificity is lost at higher concentrations. Deracoxib undergoes extensive hepatic metabolism. At 8 mg/kg (approximately 2 to 8 times the recommended dose [1 to 4 mg/kg]), nonlinear kinetics emerge, increasing the risk of toxicity. As with other NSAIDs, gastrointestinal toxicity occurs with increased doses. The package insert indicates that toxicity occurs at 3 times the dose when a micronized (which differs from the approved product) compound was administered (in a rapidly dissolving capsule) but not when the commercial preparation was administered at the same dose (see Table 29-5). Whether or not derocoxib is more likely than other NSAIDs to reach saturation kinetics is not known. The difference in preparations may have resulted in much more rapid exposure of the gastrointestinal mucosa to drug. The gastrointestinal lesions associated with the micronized material were attributed to a local effect (osmotic, pH, pharmacologic, others) rather than a systemic effect.²⁰⁵ Dose-dependent increases in blood urea nitrogen were reported when dogs received deracoxib at 3, 4, and 5 times the recommended dose (2 mg/kg); variable renal histologic lesions were reported. The disposition of deracoxib has been described in cats after a single oral dose (see Table 29-4). ²⁰⁶ Safety information in cats was not available at the time of this publication other than at the FDA CVM site (Table 29-6).

As a sulfonamide, deracoxib might be expected to be associated with adverse reactions (but not those typical of antimicrobial sulfonamides), including keratitis sicca.

In a study at least partially funded by the manufacturer, efficacy of deracoxib administered as a single dose (0.3, 1, 3, or 10 mg/kg) was compared with that of carprofen (2.2 mg/kg) in 24 hound dogs. Drugs were administered 30 minutes before induction of chemically induced (urate crystal) synovitis, and lameness indices (including clinical scores, force plate analysis, and joint fluid analysis) were measured for 24 hours after induction. Deracoxib was found to be somewhat more effective at 3 mg/kg (determined to be the minimum effective dose) and more effective than carprofen at 10 mg/kg (not a recommended dose) on the basis of outcome measures for lameness which included lameness scores, pain joint effusions, and pain threshold response²⁰⁷; no significant differences were found between carprofen or the placebo group.

Lascelles and coworkers⁸⁰ described a series of cases of gastrointestinal perforation associated with deraxocib administration in dogs (n = 29). The mean age was 6.4 ± 3.2 years. Among the more important points of the report was that 55% of the dogs received a dose higher than recommended on the label; and 59% had received, within the previous 24 hours, either a different NSAID or a glucocorticoid. A total of 90% of the dogs had received one or the other and a total of 20% had received both. Of the dogs, 68% either died or were euthanized. The mean dose in dogs receiving the drug for long-term pain management was 3± 1.1 mg/kg/day, ranging from 2.3 to 6.2 mg/kg.

The safety of deracoxib (1.5 mgkg daily) was prospectively compared with that of buffered aspirin and placebo (25 mg/kg orally every 8 hours) in dogs (placebo controlled) based on gastroscopy and clinical scores assessing vomiting and diarrhea.²⁰⁸ Aspirin-related gastric lesions and vomiting were higher than similar lesions in the deracoxib-treated and placebo-treated groups, beginning with the first endoscopic exam at 6 days.

Etodolac

Etodolac is a pyranocarboxylic acid that has shown potent NSAID activity by inhibiting chondrocyte and synoviocyte biosynthesis of PGE₂ COX-1 to COX-2 ratios vary among studies. The ratio using human cells appears to favor safety,²⁰⁹ although studies using canine cells³² reveal the opposite. Ricketts and coworkers³² reported a COX-1 to COX-2 ratio of only 0.517 compared with 129 for carprofen (study sponsored by carprofen manufacturer). In dogs the drug is rapidly absorbed, with food slowing absorption. Its elimination half-life is approximately 14 hours,²¹⁰ which is sufficiently long to allow once-daily dosing. Food may prolong elimination (see Table 29-4). The drug is extensively metabolized, with the majority eliminated in the bile and up to 10% excreted in the urine; enterohepatic elimination is extensive, potentially increasing the risk of gastrointestinal toxicity.¹²⁷ Etodolac is marketed as a racemic mixture, although the disposition of the enantiomers has not been well described in animals. Because it is approved for use in humans, much information is available regarding possible side effects in humans. However, in vitro studies indicate pharmacodynamic effects may differ in animals, and extrapolation of information may be inappropriate. Because of its longer half-life and enterohepatic elimination, etodolac may be associated with a greater risk of gastroduodenal ulceration than other COX-2 preferntial drugs. Toxicity studies also suggest that etodolac may not be as safe as other newer NSAIDs, which might be supported by COX ratios in the dog (see Table 29-3). According to the package insert, six of eight dogs developed gastrointestinal erosions and subsequently died after etodolac was administered at five times the recommended dose for 6 to 9 months (see Table 29-5). Five of six dogs developed excessive bleeding when receiving etodolac at the recommended dose, although the duration of therapy was not clear from the package insert. However, clinically, based on field studies, etodolac does not appear to be less safe than the other COX-2 preferential drugs.

Liver disease in dogs such as that associated with carprofen has not been reported in the literature but has been anecdotally reported and has been seen by the author. Etodolac (mean dose of 13.7 mg/kg orally every 24 hours for 28 days) administration did not significantly affect serum T₄, T₃, fT₄, or cTSH concentrations or serum osmolality in healthy random-source mixed breed dogs (n = 19). However, plasma total protein, albumin, and globulin concentrations were decreased by day 14 of administration; decreases were still evident by day 28 of administration, although all concentrations were within normal limits.¹¹⁸ The effect of etodolac on cartilage metabolism has not been well documented, although one study found it to be associated with more cartilage damage than carprofen.²¹¹ Etodolac has been associated with keratitis sicca. ^211a In a series of cases collected from the manufacturer or surveyed veterinary ophthalmologists, lesions were commonly considered severe, occurred in both eyes more than 50% of the time, with remission occurring in 10 to 15% of animals. Remission was 4 times more likely if treatment duration was less than 6 months.

Etodolac is available of an oral capsule prepration for use in dogs. Despite potential gastrointestinal adverse drug events, when dosed at 10 to 15 mg/kg once daily, etodolac was effective yet safe for controlling lameness associated with hip dysplasia.²¹² A clinical trial comparing carprofen and etodolac was previously discussed (see carprofen).¹⁹⁶ Aragon and coworkers¹⁹⁸ ranked etodolac as moderate with regard to scientific evidence of efficacy claims.

Firocoxib

Firocoxib has recently been approved for use in dogs in a chewable tablet form. Its disposition was reported before its approval by McCann and coworkers,²¹³ who reported on COX-2 selectivity (canine whole blood), pharmacokinetic properties (2 mg/kg intravenously and 8 mg/kg orally) in healthy male and female mixed-breed dogs (n = 21). The IC₉₀ for COX-2, according to the monograph, is 0.3 μg/mL, compared with a C_max of about 0.5μg/mL at the recommended dose in dogs (Table 29-4). In the manufacturer sponsored study, the COX-1 to COX-2 ratio using canine blood was 384, compared with 6 for carprofen and 12 for deracoxib. Although the volume of distribution is larger than for most NSAIDs, clearance also is rapid, resulting in a relatively short half-life compared with that of other NSAIDs (see Table 29-4). Nonetheless, the drug is administered once a day. The oral bioavailability of firoxocib as listed on the package insert at 5 mg/kg is 38% (variability not reported); as such, care may be indicated in anticipating potential differences in oral bioavailability among animals.^∗

Firocoxib is approved for use in dogs greater than 3.2 kg (smaller dogs cannot be accurately dosed) as a chewable tablet. The package insert overdose data and its impact on gastssrointestinal toxicity for firocoxib are indicated in Table 29-5. The manufacturer of firocoxib was interested in avoiding an age limit to drug administration, and accordingly, studied firoxocib in juvenile Beagle dogs (Table 29-5). Fatty livers were consistent findings in drug-treated juvenile dogs. In addition to the gastrointestinal effects, one juvenile dog given a dose 3 times that recommended developed juvenile polyarthritis, thrombocytopenia, decreased albumin, and elevated liver enzymes. In a separate study, one dog receiving 3 times the dose was euthanized because of poor clinical condition, although no indication was given as to whether adversity was related to the drug. However, 4 of 12 juvenile dogs receiving 5 times the dose either died (n = 1) or were euthanized (on account of a moribund status) as early as day 38 and as late as day 79; two of the dogs had gastrointestinal ulceration. This data should not be interpreted as a greater risk of toxicity to firocoxib as much as a potential indication that NSAIDs should be avoided in animals 6 months or younger.

For the approval process, efficacy of firocoxib was compared at 8 mg/kg with carprofen (2.2 mg/kg) as the positive control in healthy male Beagles (n = 24; eight per group) using chemically induced (urate) synovitis. The drugs were administered either prophylactically (administration 2 hours before induction of synovitis) or therapeutically (administration 1 hour after induction). Both drugs were effective in controlling pain and inflammation when administered either prophylactically or therapeutically; failure to find a difference between the two NSAIDs was attributed to the variability in the data compared to animal numbers studied. Although a treatment effect was found across time for firocoxib compared with carprofen, superiority of firocoxib compared with carprofen was not sufficient to allow label claims as such. Pollmeier and coworkers,²¹⁴ in a manufacturer-sponsored study, reported the results of a multicenter field trial that compared firocoxib (5 mg/kg/day) to carprofen (4 mg/kg/day) using a double-blinded, randomized design in dogs (n = 218) with osteoarthritis. Efficacy was assessed by both owners and veterinarians. Reponse was slightly better for firocoxib at 96% compared with 92% for carprofen.

Meloxicam

Robenacoxib

Robenacoxib is approved for use in companion animals outside the United States.^45,234 The disposition of robenacoxib has been described in dogs after single-dose administration of 1 mg/kg either orally (fasted or fed), intravenously, or subcutaneously²³⁵ (see Table 29-4). Isoform preference in studies supported by the manufacturer indicate a COX-1 to COX-2 ratio (95% inhibition) of 450 using whole blood assays in cats.⁴⁵ The disposition of robenacoxib in cats at 2 mg/kg intravenously has been reported.⁴⁵ Data from the ex vivo and pharmacokinetic studies were subsequently integrated with a model of inflammation in cats (n=10), resulting in a recommended dose 2 mg/kg dose every 12 hours.

Vedaprofen

Vedaprofen is marketed outside the United States for use in dogs as an oral gel preparation. A document provided by the manufacturer indicates that the racemic mixture is approximately 8 times more potent toward COX-2 than COX-1, with the majority of activity exihibited by the S enantiomer. The pharmacokinetics of vedaprofen, including its enantiomers, are available in the dog (see Table 29-4)²³⁶ after administration either intravenously or as an oral gel preparation. Although volume of distribution was not provided, the elimination (disappearance) half-life was 12 to 17 hours, depending on oral versus intravenous administration. Bioavailability of the gel preparation was near complete. The S and R enantiomers are present generally at a ratio of 1:1, with variability ranging as low as 0.5 (toward the end of the 24-hour dosing interval) and as high as 3.10 (at 2 to 3 hours) after single dosing. After oral multiple dosing for 14 days, the R:S ratio averaged about 1.8 throughout the 24-hour dosing interval. The higher concentration of the R enantiomer appears to reflect more rapid clearance of the S enantiomer (see Table 29-4). The dispositionof vedaprofen did not appear to change substantially with 14 days of dosing.²³⁶ The efficacy and safety of vedaprofen were compared with that of meloxicam, which was used as the control during the approval process. Differences could not be detected for either safety or efficacy. Gastrointestinal side effects were reported in approximately 11 to 12% for both groups despite treatment for approximately 15 days (acute) and 40 days (chronic). Both drugs were effective in both acute (approximately 88%) and chronic (approximately 67%).²³⁷

Celecoxib

Celecoxib appears to be COX-1 sparing in the dog (see Table 29-3).Its disposition has been studied in Beagles after single and multiple oral dosing, using different (a solution and solid) dosing forms, with and without food.²³⁸ Celecoxib metabolism in dogs is characterized by polymorphism: Paulson and coworkers⁴¹ described dogs that metabolize the drug poorly (poor metabolizers [PMs]) compared with efficient metabolizers (EMs). The elimination half-life of the drug in PMs is approximately 4 times as long as that in EMs (see Table 29-4). The drug is normally extensively metabolized (principally hydroxylation followed by oxidation). In both EMs and PMs, approximately 80% of the drug is eliminated in the feces. In EMs disposition does not appear to change with chronic (1-year) dosing. Administration of the drug with a fatty meal increased both the C_max and the bioavailability. The disposition of celecoxib also has been studied in normal Greyhounds after single (12.5 mg/kg) and multiple dosing. Decreases occurred in C_max (22%), elimination half-life (shorter), and area under the curve (40%) after 10 days of dosing at 12.5 mg/kg per day.²³⁹ The pharmacodynamic and toxic effects of celecoxib have not been well studied in the dog.

Rofecoxib

Rofecoxib is described as a COX-2–selective drug in humans, but no information is available regarding its selectivity in dogs. Its disposition has been studied in dogs (see Table 29-4).²⁴¹ The drug is cleared after oral administration primarily by biliary excretion after extensive hepatic metabolism to hydroxyl and glucuronide metabolites, with some urinary excretion.²⁴¹ The effects of rofecoxib (0.5 mg/kg/day orally) on the canine gastrointestinal tract were compared endoscopically to those of the dual-acting NSAID licofelone (2.5 mg/kg orally twice daily) and placebo after 56 days of dosing.²⁴⁰ Whereas no endoscopic lesions were evident for either the placebo or licofelone, rofecoxib was associated with lesions in both the gastric (six of seven) and duodenal (four of seven) areas. This occurred despite a progressive decline in mean plasma drug concentrations for rofecoxib across time: Baseline concentrations were 110.1 ± 85.8 (2 days) compared with study end concentrations of 65.3 ± 49.1 ng/mL (56 days). Concentrations of licofelone also decreased: 761.0 ± 413.8 at baseline compared with 307 ± 106.5 ng/mL at study end.²⁴⁰

Nimesulide

Nimesulide is a COX-2–selective drug approved for use in humans that also appears to act as a COX-1–sparing drug in dogs.^31,242 The disposition of nimesulide has been studied in dogs (n = 8-10) after single-dose administration of 5 mg/kg intravenously, intramuscularly, and orally and after 5 days of once-daily administration of the same dose (see Table 29-4).²⁴² The terminal elimination half-life after intramuscular administration was longer than that after intravenous administration, indicating a flip-flop model for this route. On the basis of the integration of pharmacokinetics and pharmacodynamics, the authors determined an effective concentration (EC₅₀) to be 2 to 6 μg/mL, which would be achieved at the studied dose, with some inhibition of COX-1 also occurring.²⁴³ However, the study was performed on Beagles, which may not be generally applicable to the canine population at large. The safety of nimesulide has not apparently been studied in dogs.

Leukotriene Formation

Although COX has been the primary target of NSAIDs, the complex role of lipoxygenases in the inflammatory process increasingly is being recognized and targeted. Further, improved gastrointestinal safety as a result of inhibition of leukotrienes supports their potential use. Goodman and coworkers²⁵⁸ recently reviewed the role of LTs and their inhibition in dogs and cats.

Lipoxygenase enzymes located within cells can also metabolize AA to inflammatory mediators, with lipoxygnases 5, 12, and 17 apparently being the most clinically relevant.^7,8,17,259 Lipoxygenase enzymes are not as ubiquitous in the body as the COX enzymes, but the enzymes do vary in tissues location. Lipoxygenase-5 enzymes are found primarily in cells of myeloid origin, including macrophages (and all tissues in which they are found) as well as B-lymphocytes. The initial product formed from its action on AA is HPETE, followed by LT A4 (Figure 29-10; see also Figures 29-1 and 29-2). Further conversion (by way of hydroxylase) of LTA4 produces LTB4, a very potent chemotactant, and LTC4 (by way of reduced glutathione) or LTD4 (γ-glutamyltranspeptidase). From these, LTD4 is further converted to LTE4. LTs C, D, and E are referred to as cysteinyl-LTs (see Figure 29-2).²² A second lipoxygenase enzyme, lipoxygenase-12, occurs in platelets, where it catalyzes the formation of 12-HPETE.^7,22 A third enzyme, lipoxygenase-15, catalyzes the formation of lipoxins. In contrast to LTs, lipoxins (LXA₄ and LXB₄) are characterized by anti-inflammatory activity.²⁶⁰ Lipoxin formation can occur when 5-lipoxygenase products interact with 12- lipoxygenase or 15- lipoxygenase.²⁶¹ Lipoxins are described as counterregulatory, with a particular focus on those inflammatory responses that resolve inflammation.²⁶⁰ LTs act through membrane receptors located on inflammatory and other cells. Receptors are linked to G proteins, increasing intracellular calcium and decreasing cAMP (see Figure 29-1). For example, LTB4 binds to BLT1 and 2 subreceptor types located in inflammatory cells, whereas cysteinyl LTs (C-E) bind to CysLT1 and 2 subreceptor types located in eosinophils, macrophages, and bronchial smooth muscle.

Figure 29-10 Acetaminophen toxicity reflects a cytotoxic type A adverse reaction. Because cats are deficient in glucuronidation, phase II metabolism is easily overwhelmed, and drug is shunted more aggressively back into phase I metabolism. The same process occurs in dogs after an overdose. The products of phase I metabolism are reactive and cause destruction of tissues (liver and red blood cells). Glutathione, an important phase II scavenger, prevents damage but is easily depleted in cats. Supplementation in the form of N-acetylcysteine can decrease damage. Cimetidine is useful because it decreases phase I metabolism and thus the formation of phase I metabolites.

Leukotrienes in Health and Disease

With the exception of lipoxins, each of the lipoxygenase-catalyzed products is a potent mediator of inflammation. At picomolar concentrations, they are effective in the activation, recruitment, migration, and adhesion of immune cells.²² LTs and other selected lipoxygenase products modulate lymphocyte function.⁸ LTB4 increases production and release of inflammatory cytokines, including activation of NF-kB (transcription factor responsible for expression of proinflammatory cytokins), and expression of TNF-alpha and IL-1β. In the cartilage these cytokines increase expression of MMPs.¹⁸ Inhibition of 5-lipoxygenase reduces expression of the cytokines, including TNF-alpha.²² In addition to their effect on leukocytes, the cysteinyl LTs are extremely spasmogenic, causing bronchoconstriction (being 100 times more potent than histamine) in the lungs and exacerbation of ulcerogenic effects in the gastrointestinal tract. The cysteinyl LTs are important mediators in hypersensitivity reactions. They are particularly effective chemoattractants for eosinophils; as such, they play important roles in a number of inflammatory and allergic diseases.²⁵⁸ LTB4 most commony is associated with inflammation associated with inflammatory bowel lesions; colonic epithelials cells are able to produce LTB4. A potential role for lipoxygenase in cancer also is emerging: Lipoxygenase-5 is overexpressed in cancer cells; upregulation in pancreatic cancer suggests a potential therapeutic role for lipoxygenase inhibitors.^24,258,262 The role of LTs in eosinophil signaling and chronic (allergic) inflammatory diseases is discussed in Chapter 31.

A potential sequela of COX blockade by NSAIDs is shunting of unused AA to the lipoxygenase pathway, resulting in increased production of LTs from AA that would have otherwise been metabolized to PG products.⁸ For example, aspirin hypersensitivity has been associated with the diversion of AA from the PG to the LT (5-lipoxygenase) pathway and the production of mediators that are more inflammatory than the products of PGH synthetase.^10,22 Aspirin hypersensitivity also has been attributed to the loss of PGs that might otherwise have specifically inhibited the formation of LTs. The adverse reactions of NSAIDs thus reflect not only loss of PGs but also augmentation of LT synthesis.⁸ Examples include exacerbation of bronchoconstriction and increasing ulcerogenicity of NSAIDs. Newer NSAIDs that preferentially target COX-2 are not characterized by aspirin hypersensitivity, presumably because AA can yet be metabolized to PGs by way of COX-1.

Lipoxygenase Inhibition

Originally, studies indicated that NSAIDs were not capable of inhibiting LT synthesis. However, the antiinflammatory efficacy of some of the NSAIDs (e.g., ketoprofen)²⁶³ has been attributed, in part, to inhibition of lipoxygenase and thus prevention of LT formation.⁶ However, the ability of NSAIDs to inhibit 5-lipoxygenase is controversial.⁸ More recently, dual-acting NSAIDs, which impair COX-1 and -2 and lipoxygenases, have been approved. These include tepoxalin, which was initially studied in humans, but approved only for use in dogs. The class of di-tert-butylphenol antiinflammatory agents have the added advantage of antioxidant (phenolic properties) and radical-scavenging properties.²² These include tebufelone, darbufelone, and licofelone. Finally, the effects of LTs can be inhibited at the level of the receptor. LT-receptor antagonists include zafirlukast and montelukast (Figure 29-11).

Figure 29-11 Structures of selected drugs used to treat various aspects of inflammation. Antihistamines are generally structurally similar to histamine (upper left).

Lipoxygenase Inhibitors

Zileuton is a potent, selective 5-lipoxygenase inhibitor. It is the only drug of this class approved for use in the United States. Use of these drugs has largely been limited by hepatotoxicity; further, efficacy has been limited.

Dual-Acting Nonsteroidal Antiinflammatory Drugs

Despite the advantages of NSAIDs that COX-1–sparing drugs offer, the need for improved gastrointestinal tolerance continues. Because the formation of LTs from AA that might otherwise have been metabolized to PGs appears to contribute to the toxicity (gastrointestinal, repiratory, and other) of NSAIDs (conventional more so than newer drugs), a drug with both COX and lipoxygenase inhibitory effects has been the target of the pharmaceutical industry for some time. However, the presence of an iron atom in the structure of COX or lipoxygenase required that such drugs be redox active in their mechanism. Therefore these drugs tended to inhibit other redox-active enzyme systems, including those in the liver. Consequently, hepatotoxicy has limited the use of dual-acting drugs. Two drugs have been studied in human medicine for their dual actions: tepoxalin and licofelone. The latter is an AA substrate and as such acts as a competitive inhibitor of COX and lipoxygenase without redox activity;⁸¹ it is not clear whether tepoxalin similarly avoids redox activity. Neither drugs target lipoxygenase-12 or -15, and thus minimally affect lipoxin formation, further improving potential gastrointestinal tolerance. Further, in the cardiovascular system, because both COX-1 and COX-2 (prostacyclin and thromboxane formation) are inhibited, thrombembolic balance should not be disrupted.

In addition to enhanced safety, enhanced efficacy of dual-acting NSAIDs toward inflammatory diseases should be anticipated. As such has been demonstrated for licofelone in experimentally induced osteoarthritis in dogs. Not only are LT and PG formation decreased, but also formation of proinflammatory cytokines is decreased. Their ability to inhibit both COX and lipoxygenase may result in synergistic activity in the control of inflammation.²⁶⁴ Preliminary data suggest that dual inhibitors may slow the progression of osteoarthritis.²⁶⁵ Because of their potential enhanced efficacy and safety, dual inhibiting NSAIDs have been referred to as a class of breakthrough NSAIDs.²² Indications for dual inhibitors include osteoarthritis, the chronic inflammatory allergic diseases asthma and atopy, and chronic inflammatory bowel disease.

Leukotriene Receptor Antagonists

Zafirlukast and montelukast are competitive cysLT-1 receptor antagonists (LAR) approved for use to treat human asthma. However, their use increasingly is being expanded to treatment of a variety of chronic allergic inflammatory diseases. Interestingly, their use might be considered in combination with NSAIDs to reduce the risk of gastrointestinal toxicity. The currently available LARs are available only for oral administration. Disposition information is not available for dogs or cats. In humans the drugs are rapidly and nearly completely absorbed. Metabolism of zafirlukast is by CYP2C9 and for montelukast by CYP3A4 and CYP29C. Metabolites are not active. Half-lives in humans are 10 hours (zafirlukast) and 3 to 6 hours (montelukast). Maximum efficacy may require 2 to 4 weeks, although an initial response may be evident within several days. The drugs are generally very safe, probably reflecting the limited effects of LTs in the body.²⁷⁰

Histamine in Health and Disease

Histamine is a low-molecular-weight amine, synthesized from histidine by its decarboxylation. Histidine decarboxylase is ubiquitous in the body, occuring in the CNS, gastric parietal cells, mast cells, and basophils. Upon its formation histamine is stored. Most histamine is stored bound to heparin in granules located in either mast cells or their circulatory counterparts, basophils. Histamine is not the sole mediator of clinical relevance located in mast cells. Because histamine release occurs by mast cell degranulation, it is accompanied by the release of other mediators, including those preformed and stored in granules (e.g., serotonin) and those synthesized in situ (e.g., AA products). Currently, four histamine subreceptors have been identified. The H₁ receptors couple to G proteins, activating the PLC–IP3–Ca²⁺ pathway [G&G].²⁷⁸ H₂ receptors link to Gs, activating the adenylyl cyclase cAMP pathway. Both H₃ and H₄ receptors are inhibitory toward adenylyl cyclase; 35% or more homology between the two complicates pharmacologic distinction.

The impact of antihistamines is complex but somewhat predictable based on the location and impact of each receptor. For example, H₁ receptors on vascular endothelium activate calcium mobilization and nitric oxide production (eNOS), causing local vascular smooth muscle relaxation. In contrast, activation of H₁ receptors in smooth muscle will cause contraction (e.g., bronchoconstriction), which is balanced by stimulation of H₂ receptors in the same cells that mediate relaxation. Both H₁ and H₂ receptors are distributed throughout the peripheral nervous system and CNS, whereas H₃ receptors are limited to the CNS. The H₃ receptors serve as autoreceptors. In general, their stimulation promotes sleep, and antagonism is manifested as wakefulness. H₄ receptors are located primarily in cells of hematopoietic origin.²⁷⁸ These include granulocytes. Stimulation of H₄ receptors on eosinophils induces a change in the shape of the cell, chemotaxis, and upregulation of adhesion molecules; antagonists therefore may be particularly useful for treatment of chronic allergic diseases.

The effects of histamine on H₁ and H₂ receptors vary with the site and extent of release. In general, histamine affinity for H₁ receptors is probably greater than that for H₂ receptors. In the vasculature both H₁ and H₂ receptor activation causes relaxation of arteriolar smooth muscle (resistance vessels), resulting in vasodilation. Whereas H₁-mediated responses are rapid, H₂- mediated response are slow and prolonged. In contrast to its effect on smaller vessels, histamine may cause contraction of the smooth muscle, causing hypertension in some species. In the heart contractility and automaticity increase, primarily through H₂ receptors. Endothelial cells of venules contain more histamine receptors than other tissues. In postcapillary venules, H₁ receptors cause endothelial cells to contract and separate, regulating cell-to-cell cytoskeleton interactions.^278a The loss of the endothelial barrier results in increased permeability, typical of edema. Passage of inflammatory cells into tissues is facilitated. In nonvascular smooth muscle, H₁ receptors cause contraction, whereas H₂ receptor activation causes relaxation. Thus in the bronchi the predominant effect of smooth muscle contraction is bronchoconstriction; in the gastrointestinal tract, diarrhea may occur. Species sensitivity to these effects vary; for example, histamine does not appear to play a major role in bronchoconstriction associated with asthma in the cat. Release of histamine from mast cells and basophils causes H₂-mediated inhibition of further histamine release. Gastric acid secretion is mediated by H₂ receptors. The H₁ receptors also stimulate sensory nerve endings; for example, pruritis reflects, in part, stimulation of type C nerve fibers.

The manifestation of the vascular effects of histamine varies depending on the magnitude of response. Local effects in the skin are manifested as the typical wheal and flare response; in contrast, systemic release, if sufficient, may be manifested as hypotensive shock, typical of anaphylactic or anaphylactoid response. The clinical signs vary with the species, depending on the “shock” organ, which in turn generally reflects the tissue with the greatest number of mast cells (lungs in cats, gastrointestinal tract in dogs).

Prevention or treatment of the effects of histamine can be accomplished in several ways: preventing histamine release (e.g., inhibition of mast cell degranulation), targeting the histamine receptor itself, or antagonizing (modulating) tissue response to histamine (e.g., the use of beta antagonists to blunt histamine-induced bronchoconstriction). Of these, the most comprehensive response is likely to occur if mast cell degranulation is prevented. This reflects the fact that histamine is not the only mediator released with degranulation. Others simultaneously released include those stored with histamine, such as serotonin (to which feline bronchial smooth muscle has been described as very sensitive), and those mediators formed in situ (e.g., eicosanoid mediators such as PGs, LTs [LTB4], or slow-reactive substance of anaphylaxis), platelet activating factor, and related compounds (see Figure 29-1)

Inhibitors of histamine release (mast cell degranulation) (see Figure 29-1), are exemplified by cromolyn sodium. It prevents calcium-dependent release of histamine from mast cells (but not basophils). Its mechanism of action may involve inhibition of calcium flux into the mast cell. Because degranulation is prevented, the release of other autacoids released with histamine is also prevented. However, the drug is poorly absorbed orally and can be given only by inhalation. Thus its use is limited to respiratory disease associated with mast cells. Because it prevents degranulation, it is useful only when administered prophylactically.

Structure–Activity Relationship

Anthistamines historically refer to those drugs specific for H₁ receptors. Some of the drugs also inhibit muscarinic, serotonin, or alpha-adrenergic receptors. All H₁ receptor blockers or antagonists are structurally similar to histamine; however, the primary amine of histamine is replaced by a tertiary amine (see Figure 29-11). Previously referred to as competitive antagonists at histamine receptors, they are now described as inverse agonists. They preferentially bind to the receptor in its inactive state, maintaining the conformation of the inactive state, thus prolonging the state of inactivity.²⁰⁵ Antihistamines are among the most used drugs in human medicine, with over 40 different drugs available worldwide, many of them nonprescription. Traditional categorization results in six chemical groups: ethanolamines, ethylenediamines, alkylamines, piperazines, piperidines, and phenothiazines. Alternatively, another classification is based on sedative potential, with first-generation drugs being sedating and second-generation drugs being nonsedating.

Pharmacologic Effects

The effects of the H₁ receptor blockers are similar and predictable regardless of the preparation. Specific effects include smooth muscle inhibition in the gastrointestinal tract and respiratory tract; inhibition of histamine-induced vasodilation of resistance vessels in the vasculature (residual vasodilation may require H₂ blockers); and strong antagonism of capillary and venule permeability. In the CNS both stimulation and depression may occur, depending on the drug. However, second-generation drugs (particularly cetirizine or fexofenadine, but less so loratadine) do not penetrate the blood–brain barrier and are less likely to be associated with CNS side effects.²⁷⁹ The difference appears to reflect, in part, whether the drugs are substrates for P-glycoprotein, with second-generation drugs more likely. Effects on anaphylactic (or anaphylactoid) shock vary with species and tissues. Inhibition of motion sickness may actually reflect anticholinergic activity (promethazine). Antiallergic effects of the newer drugs in particular may reflect inhibition of mediator release,²⁰⁵ probably by way of direct inhibition of inward calcium flux through calcium ion channels.

Example drugs include doxepin (marketed as a tricyclic antidepressant), diphenhydramine (antimuscarinic and sedating ethanolamine), chlorpheniramine (first-generation alkylamine; such drugs as a class are very potent and less sedating), hydroxyzine, cyclizine, and meclizine (a first generation piperazines), cetirizine (a second-generation piperazine and active metabolite of hydroxyzine), promethazine (a phenothiazine), cyproheptadine (a first-generation piperazine that also has antiserotonergic effects), and terfenadine (a second-generation piperazine). Dimenhydrinate (Dramamine) and diphenhydramine (Benadryl) are characterized by marked sedation and significant antimuscarinic effects. Tripelennamine is one of the most specific H₁ antagonists and is associated with less sedation but more gastric side effects. Chlorpheniramine is one of the most potent H₁ blockers and also is associated with less sedation but more CNS stimulation. Promethazine is the most potent inhibitor of motion sickness. Piperazines are very effective for motion sickness and may have more prolonged action (cyclizine and meclizine). Phenothiazines (promethazine as the prototype) are characterized by considerable anticholinergic activity and prominent sedation but are the most effective for motion sickness.

Pharmacokinetics

Few antihistamines have been studied in animals. Species differences are likely to preclude extrapolation of dosing regimens among species, and particularly between humans and dogs. This reflects, in part, differences in pH of the human skin (4.8) versus canine skin (similar to plasma). As weak bases, antihistamines are likely to accumulate in skin.²⁸⁰ In the ionized form, the accumulated drug will be inactive in human skin. However, the skin may serve as a depot, allowing slow release as the unionized, active form. This may either prolong elimination half-life from plasma or, if concentrations are too low to be detected in plasma, may allow a local pharmacodynamic effect that exceeds the duration indicated by pharmacokinetics. These benefits may not be realized in dogs.

Hydroxyzine is a piperazine antihistaminergic drug that is further metabolized to cetirizine, the active ingredient in Zyrtec. Its disposition has been described in dogs (n = 6) after oral and intravenous administration of 2 mg/kg hydroxyzine, using a randomized crossover design (14-day washout between routes).²⁸¹ The pharmacokinetic study was accompanied by pharmacodynamic response based on immunoglobulin E (IgE) cutaneous wheal formation. Dogs tolerated each dose well. The maximum response to hydroxyzine occurred during the first 8 hours, correlating with plasma cetirizine concentrations that exceeded 1.5 μg/mL, with response attributed almost exclusively to cetirazine. Accordingly, the authors recommended cetirizine at 2 mg/kg twice daily.

In cats the disposition of cetrizine has been described after an oral dose of 0.9 ± 0.2 mg/kg (see Table 29-4).²⁸² Despite the high proportion of bound drug, the effective concentration in humans of 10.5 to 27.3 ng/mL was achieved (based on calculation of free drug) and maintained during a 24-hour dosing period. Cats tolerated the single dose well, despite drug concentrations that are higher than those generally achieved in humans (human dose 10 mg/person).

Clemastine is an ethanolamine antihistaminergic drug. Its disposition and pharmacodynamic response have been described in dogs (Table 29-7).²⁸⁰ Target concentrations in human approximate 0.7 ng/mL. After oral administration bioavailability of clemastine was less than 5%. Although not reported, plasma drug concentrations versus time curves indicate that 0.7 ng/mL is achieved but maintained for less than 3 hours in dogs after oral absorption. Poor oral absorption contributed to poor response to antigen challenge, whereas intravenous administration inhibited wheal formation entirely for 7 hours. Accordingly, the oral dose of the drug should be at least 1 mg/kg every 12 hours or more; in contrast, the intravenous dose of 0.1 mg/kg would be effective twice daily.

Table 29-7 Pharmacokinetic Data for Selected Antihistamines In Dogs and Cats

Drug Interactions

Antihistamines generally are substrates for P-glycoprotein and other drug transport systems; therefore competition should be expected when they are used in concert with other P-glycoprotein substrates. Selected drugs may also cause the induction or inhibition of drug-metabolizing enzymes.

Adverse Drug Reactions and Side Effects

Because side effects to first-generation drugs are problematic, alternative drugs were developed. For example, diphenhydramine adversely affects learning in children and alters cognition and mood. Several drugs cause a level of intoxication similar to that produced by alcohol; chlorpheniramine causes a hangover effect. Gastrointestinal side effects include anorexia, nausea and vomiting, constipation, and diarrhea. Other effects, such as a dry respiratory tract and urinary retention or dysuria, can be attributed to atropine-like (anticholinergic), antiadrenergic, and antiserotonin effects. Newer antihistamines (H₁) do not interact with muscarinic receptors as effectively as did the first-generation drugs, thus avoiding many of these side effects. Side effects in the CNS are not unusual at therapeutic doses. However, they are rarely serious, and adaptation occurs with chronic use. Sedation is affected by pH, lipophilicity, and activity of transport proteins such as P-glycoprotein.²⁸³ Lack of sedation in the newer drugs has been attributed to transport proteins that mediate active efflux from the CNS and thus limit CNS distribution. Collies and related breeds deficient in P-glycoprotein might be expected to manifest more CNS reactions with newer drugs compared with other dog breeds.

Two early second-generation H₁ antihistamines, astemizole and terfenadine, were associated with cardiotoxicity (prolongation of the QT interval: torsades de pointes) as a result of blockade of the rapid component of the delayed rectifier potassium current. More recent drugs, including loratadine, desloratadine (a metabolite of loratadine), cetirizine, and fexofenadine (a metabolite of terfenadine), are not associated with this effect.

Acute poisoning is not uncommon in humans; its occurrence in dogs and cats is not known. There is no specific therapy. Signs include ataxia, incoordination, convulsions, dry mouth, and fever, with treatment being supportive.

Therapeutic Use

Indications for antihistamines include the prevention or treatment of anaphylactic shock (IgE-mediated histamine release) or anaphylactoid response (e.g., cationic drug-induced histamine release), motion sickness (see the discussion of the gastrointestinal tract), particularly dimenhydrinate, piperazines, and promethazine, and allergic disease, including that affecting the skin. These indications are addressed in the relevant chapters. Antihistaminergic drugs have proved variably useful in the control of small animal allergic diseases.^284-286 This no doubt reflects differences in receptors and drug receptor interactions. However, profound differences also are likely in the disposition of the drugs, including oral bioavailability (e.g., clemastine in dogs). Part of the lack of efficacy also reflects limited actions: Although the effects of histamine at H₁ receptors may be blocked, limited to no effects on mast cell degranulation will result in inflammatory response to other mediators.