Page 399 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

366 SECTION | IV Drugs of Use and Abuse

VetBooks.ir platelet COX irreversibly (Rubin and Papich, 1990). new class of COX 2 -specific NSAIDs was developed as a
Most NSAIDs inhibit both COX 1 and COX 2 , but a
There are three isoforms of COX; designated COX 1 ,
safer alternative. These drugs include celecoxib, deracox-
COX 2 ,andCOX 3 .COX 1 is found in almost all tissues,
including the gastrointestinal tract, platelets, endothe- ib, rofecoxib, diclofenac, etodolac, firocoxib, flosulide,
lium, and kidneys, is continuously produced, and func- and meloxicam. However, rofecoxib (Vioxx) was volun-
tions in tissue homeostasis. Most of the adverse effects tarily withdrawn from the market in 2004 due to increased
associated with NSAID use are due to inhibition of risk of adverse cardiovascular events in humans, and con-
COX 1 . Inhibition of PGE 2 promotes production of gas- troversies still exist whether other compounds of this class
tric acid and pepsin, and decreases the ability of the pose a similar risk. Selectivity is species-specific, and
mucosa to secrete mucus glycoproteins and bicarbonate thus, these new drugs sometimes cause COX 1 inhibition
and respond to injury. Impairments to mucosal circula- in domestic species (Talcott, 2006). Dogs treated with
tion due to loss of PG activity produce mucosal hypoxia deracoxib and firocoxib did have fewer clinical signs and
and thrombosis. gastric lesions than dogs treated with other NSAIDs in
Loss of the vasodilative actions of PGE 2 and PGI 2 in one study (Sennello and Leib, 2006). Interestingly, car-
the kidneys through inhibition of COX 1 leads to hypoxic profen is COX 2 -specific in dogs but not in humans
renal injury (Isaacs, 1996; Rubin and Papich, 1990). (Talcott, 2006).
Production of PG by the kidneys is relatively low. With LTs are also produced from arachidonic acid via the
the possible exception of vultures, renal pathology is most lipoxygenase pathway. 5-Lipoxygenase produces LTA4,
often associated with chronic NSAID use (Fourie et al., which is converted to LTB4, LTC4, LTD4, LTE4, and
2015). Reversible urinary incontinence and isosthenuria others. LTB4 is an important chemoattractant for neu-
was reported in a dog exposed to an unknown dose of car- trophils. Various LTs cause vasoconstriction, broncho-
profen (Hutchins et al., 2013). Renal papillary necrosis is spasm, and increased vascular permeability (Boynton
frequently seen in horses, and is often associated with et al., 1988; Strøm and Thomsen, 1990; Lees et al.,
chronic phenylbutazone use (Gunson, 1983; Rubin and 1991). Some NSAIDs inhibit lipoxygenase. It has been
Papich, 1990). This lesion is also reported in cats, dogs, found that in dogs, flunixin is a more potent inhibitor
mice, rats, gerbils, hamsters, rabbits, desert mice, pri- of LTB4-mediated neutrophil migration than phenylbu-
mates, and pigs (Brix, 2002). Renal failure in cats admin- tazone, which is more potent than indomethacin.
istered meloxicam first parenterally and then orally has Alternately, some NSAIDs actually increase LT produc-
been reported, and oral exposure to flurbiprofen was tion due to increased availability of arachidonic acid not
recently reported to cause death in cats (Dyer et al., entering the COX pathway.
2009). NSAIDs can also inhibit phosphodiesterase.
Evidence suggests that low doses of NSAIDs cause Phosphodiesterase breaks down cyclic AMP (cAMP).
degeneration of medullary interstitial cells and, later, Increased intracellular cAMP can stabilize lysosomal
damage to vascular endothelium, leading to microvascu- membranes in polymorphonuclear leukocytes, inhibiting
lar thrombosis and hypoxia. Higher doses produce more release of inflammatory products (Kore, 1990). Other
rapid endothelial damage (Brix, 2002). Dehydration is a effects of NSAIDs include inhibition of phosphatidyli-
major predisposing factor for renal papillary necrosis. nositol 3 -kinase Akt signaling, important in cytokine
0
Dehydration commonly occurs with gastrointestinal dis- pathways and cell regulation, mitogen-activated protein
ease, diuretic use, anesthesia, surgical stress, hemorrhagic kinases involved in cell regulation, peroxisome
shock, or sepsis. Other risk factors described for dogs proliferator-activated receptors, NFκB, and heat shock
include advancing age, congestive heart failure, hepatic proteins involved in transcription. NSAIDs also uncou-
cirrhosis, preexisting renal problems, hypotension, and ple oxidative phosphorylation and, thus, inhibit cellular
concurrent administration of nephrotoxic drugs such as energy production (Little et al., 2007).
gentamicin or amphotericin. Some NSAIDs have topical irritant properties. As
COX 2 is produced by macrophages, fibroblasts, weak acids, they partition to the gastric mucosa, leading
chondrocytes, endothelial cells, and some other cell to decreased hydrophobicity of mucus and thinning of the
types (Roder, 2004a). This isoform only functions mucus barrier, allowing gastric acid to penetrate to the
intermittently, and is induced by cytokines in areas epithelial layer. NSAIDs frequently cause mild and tran-
of inflammation (Isaacs, 1996; Roder, 2004a; sient liver damage associated with cholestasis and
Talcott, 2006). Inhibition of this enzyme produces increased liver enzymes (Boynton et al., 1988; Isaacs,
antipyretic, analgesic, and antiinflammatory effects 1996; Roder, 2004a). More severe problems, such as
of NSAIDs. Little is yet known about the function hepatic necrosis, are rare. Hepatotoxicity is uncommon
of COX 3 , which is present in dogs but not functional with ibuprofen in dogs. More commonly reported in dogs
in humans. is idiosyncratic hepatotoxicosis due to carprofen