Administration of NSAIDs to dogs can cause toxic effects in the gastrointestinal tract and kidneys.1–3 Toxic effects in the gastrointestinal tract may be reduced via administration of NSAIDs that preferentially inhibit COX-2.4 To the author's knowledge, the effects of such drugs on renal function in dogs (particularly dogs with disease) are not known. The finding of other authors1–3 that toxic effects in the gastrointestinal tract and kidneys develop after administration of NSAIDs to animals may be attributable to synergism among factors responsible for these effects. In particular, vomiting associated with NSAID-induced toxic effects in the gastrointestinal tract can cause volume depletion and metabolic alkalosis, which might increase toxic effects of such drugs in the kidneys.
Because COX-1 may have important effects for maintenance of GFR and RPF, a drug that preferentially inhibits COX-2 (ie, selective COX-2 inhibitor) may have less impact on kidney function versus an NSAID that nonselectively inhibits both COX isoenzymes (ie, nonselective COX inhibitor). However, in another study5 conducted by our research group that included dogs with furosemide-induced volume depletion and metabolic alkalosis, administration of a nonselective COX inhibitor (ibuprofen) and a selective COX-2 inhibitor (carprofen) to dogs caused similar, significant decreases in GFR.
Carprofen and etodolac are NSAIDs that may be prescribed for the treatment of acute and chronic pain in dogs. Analgesic effects of these drugs are mediated via inhibition of prostaglandin synthesis.6–8 The propionic acid derivative, carprofen, has 5- to 6-fold selectivity for the inhibition of COX-2,9 and this drug is typically classified as a preferential inhibitor of COX-2.10,11 Etodolac is COX-2 selective in humans and rats.12,13 It has been reported14 that etodolac is COX-1 selective in dogs, although results of other studies4,15 indicate etodolac is a preferential COX-2 inhibitor in dogs and that it is less selective for the inhibition of COX-2 than is carprofen.16 However, the effects of NSAIDs and their relative selectivities for COX isoenzymes may be tissue specific. Because etodolac may be a more effective inhibitor of COX-1 in the renal vascular bed than is carprofen, etodolac may have greater adverse effects on renal hemodynamics.
The purpose of the study reported here was to determine the effects of carprofen and etodolac on renal hemodynamics in dogs. Our hypothesis was that carprofen would have a smaller effect on renal hemodynamics than would etodolac in dogs with extracellular fluid volume depletion induced by administration of furosemide.
Glomerular filtration rate
Renal plasma flow
Purina ProPlan Chicken and Rice diet, Nestlé Purina PetCare Co, St Louis, Mo.
Gelatin capsules, Eli Lilly & Co, Indianapolis, Ind.
Rimadyl, Pfizer Animal Health, Exton, Pa.
EtoGesic, Fort Dodge Animal Health, Fort Dodge, Iowa.
Salix, Intervet Inc, Millsboro, Del.
Statview, version 4.5, Abacus Concepts Inc, Berkeley Calif.
Sigma Chemical Co, St Louis, Mo.
Abbott Diagnostics, Irving, Tex.
SPR-T2 Refractometer, Atago Co Ltd, Tokyo, Japan.
Elliott GAPurmalis AVanderMeer DA, et al. The propionic acids. Gastrointestinal toxicity in various species. Toxicol Pathol 1988; 16:245–250.
Wooten JGBlikslager ATRyan KA, et al. Cyclooxygenase expression and prostanoid production in pyloric and duodenal mucosae in dogs after administration of nonsteroidal antiinflammatory drugs. Am J Vet Res 2008; 69:457–464.
Surdyk KKSloan DLBrown SA. Evaluation of the renal effects of ibuprofen and carprofen in euvolemic and volume-depleted dogs. Intern J Appl Res Vet Med 2011; 9:129–136.
Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol 1971; 231:232–235.
Brown SA. Renal effects of nonsteroidal anti-inflammatory drugs. In: Kirk RWBonagura JD, eds. Current veterinary therapy X. WB Saunders Co, 1989;1158–1161.
Bergh MSBudsberg SC. The coxib NSAIDs: potential clinical and pharmacologic importance in veterinary medicine. J Vet Intern Med 2005; 19:633–643.
Ricketts APLundy KMSeibel SB. Evaluation of selective inhibition of canine cyclooxygenase 1 and 2 by carprofen and other nonsteroidal anti-inflammatory drugs. Am J Vet Res 1998; 59:1441–1446.
Smith WLDeWitt DL. Biochemistry of prostaglandin endoperoxide H synthase-1 and synthase-2 and their differential susceptibility to nonsteroidal anti-inflammatory drugs. Semin Nephrol 1995; 15:179–194.
Dvornik DLee DK. Theoretical mechanism for the gastrointestinal safety of etodolac: selective sparing of cytoprotective prostaglandins. Clin Rheumatol 1989; 8(suppl 1):16–24.
Streppa HKJones CJBudsberg SC. Cyclooxygenase selectivity of nonsteroidal anti-inflammatory drugs in canine blood. Am J Vet Res 2002; 63:91–94.
Sessions JKReynolds LRBudsberg SC. In vivo effects of carprofen, deracoxib, and etodolac on prostanoid production in blood, gastric mucosa, and synovial fluid in dogs with chronic osteoarthritis. Am J Vet Res 2005; 66:812–817.
King JNRudaz CBorer L, et al. In vitro and ex vivo inhibition of canine cyclooxygenase isoforms by robenacoxib: a comparative study. Res Vet Sci 2010; 88:497–506.
Kendall PTBlaza SESmith PM. Comparative digestible energy requirements of adult Beagles and domestic cats for body weight maintenance. J Nutr 1983; 113:1946–1955.
Papich MG. Table of common drugs: approximate dosages. In: Kirk RWBonagura JD, eds. Kirk's current veterinary therapy XIV. St Louis: Saunders Elsevier, 2009:1306–1336.
Brown SAFinco DRBrown CA, et al. Evaluation of the effects of inhibition of angiotensin converting enzyme with enalapril in dogs with induced chronic renal insufficiency. Am J Vet Res 2003; 64:321–327.
Perazella MA. Drug-induced renal failure: update on new medications and unique mechanisms of nephrotoxicity. Am J Med Sci 2003; 325:349–362.
Barkin RLBuvanendran A. Focus on the COX-1 and COX-2 agents: renal events of nonsteroidal and anti-inflammatory drugs-NSAIDs. Am J Ther 2004; 11:124–129.
Khan KNVenturini CMBunch RT, et al. Interspecies differences in renal localization of cyclooxygenase isoforms: implications in nonsteroidal antiinflammatory drug-related nephrotoxicity. Toxicol Pathol 1998; 26:612–620.
Jones CJBudsberg SC. Physiologic characteristics and clinical importance of the cyclooxygenase isoforms in dogs and cats. J Am Vet Med Assoc 2000; 217:721–729.
Kramer BKKammerl MCKomhoff M. Renal cyclooxygenase-2 (COX-2). Physiological, pathophysiological, and clinical implications. Kidney Blood Press Res 2004; 27:43–62.
Rossat JMaillard MNussberger J, et al. Renal effects of selective cyclooxygenase-2 inhibition in normotensive salt-depleted subjects. Clin Pharmacol Ther 1999; 66:76–84.
Harris RCMcKanna JAAkai Y, et al. Cyclooxygenase-2 is associated with the macula densa of rat kidney and increases with salt restriction. J Clin Invest 1994; 94:2504–2510.