SOURCES

Since nonsteroidal antiinflammatory drugs (NSAIDs) are very popular human and veterinary drugs, either prescription or sold as over-the-counter medications, they are readily available to the pet population through misuse or accidental consumption (Table 64-1). These drugs are used for the treatment of pain, inflammation, and pyrexia. NSAIDs are classified according to their chemical structure: salicylates (e.g., aspirin), indoles (e.g., indomethacin), propionic acids (e.g., ibuprofen, naproxen, ketoprofen, and carprofen), fenamates (e.g., meclofenamic acid), pyrazolones (e.g., phenylbutazone and dipyrone), and oxicams (e.g., piroxicam and tenoxicam) (Table 64-2).^1,2 Certain drugs (ibuprofen and naproxen) that have relatively safe profiles in humans can induce serious toxicoses in dogs.^1–8 Metabolism and half-lives of NSAIDs have species differences, and doses in dogs and cats should not be extrapolated from recommended human doses.^{1,2,4,5,8–13} The following section relates mostly to the toxic effects of ibuprofen, which is still a common poisoning observed in dogs; other NSAIDs are discussed separately at the end of the chapter.

Table 64-1 Chemical Classification of NSAIDs

Table 64-2 Examples of Veterinary and Human Approved NSAIDs

TOXIC DOSE

The American Society for the Prevention of Cruelty to Animals (ASPCA) Animal Poison Control Center (APCC) received 704 calls involving suspected ibuprofen toxicoses in dogs (585) and cats (119) in a 2-year period (1986 to 1987).¹⁴ In both dogs and cats, the number of calls was 50% higher in 1987 than in 1986. The relative proportions of toxicoses and suspected toxicoses made up 45% of canine calls and 50% of feline calls.¹⁴ The ASPCA APCC listed ibuprofen among the top 25 generic agents involved in poisonings in dogs and cats in a 12-month period (January 1 to December 31, 1992).¹⁵ With the advent of newer NSAIDs, toxicoses involving other NSAIDs will ultimately be reported.

Pharmacokinetic studies of ibuprofen administration in canines revealed that the lowest dose producing gastric lesions in dogs was 8 mg/kg/day.¹³ These lesions were produced by parenteral and oral administration, thus revealing that the ulcerogenic action of ibuprofen is partly systemic. All dogs receiving 16 mg/kg/day of ibuprofen were found to have gastric ulcers on postmortem examination.¹³ As a single exposure, 50 to 125 mg/kg bw has been associated with gastrointestinal signs in dogs, and doses exceeding 250 mg/kg bw have resulted in renal damage. Cats appear to be affected at exposure doses exceeding 50 mg/kg bw.

TOXICOKINETICS AND MECHANISM OF TOXICITY

NSAIDs are a group of drugs with very different chemical structures that share many properties. The analgesic, antipyretic, and antiinflammatory actions of NSAIDs are caused by direct inhibition of cyclooxygenase (COX) inhibitors (prostaglandin endoperoxide synthase and prostaglandin synthetase).^12,16,17 NSAIDs (other than aspirin) produce reversible COX inhibition by competing with the substrate arachidonic acid for the active site of the enzyme.¹⁷ Thus NSAIDs reduce the production of prostaglandins and thromboxane.

NSAIDs differ from glucocorticoids in that glucocorticoids inhibit phospholipase, which is higher up in the inflammatory cascade. Glucocorticoids therefore inhibit lipoxygenases as well.^1,12,17,18 As Maddison notes, “There is no clinical situation where the concurrent use of corticosteroids and NSAIDs has any rational basis.¹⁸”

COX exists in two isoforms. Constitutive COX-1 is responsible for physiological functions and is expressed in most tissue. It functions in synthesizing prostaglandins that regulate normal cell activity. Inducible COX-2 is involved in inflammation. COX-2 is an enzyme that is rapidly induced at the site of inflammation and is responsible for the production of proinflammatory prostaglandins.^17–21 Most NSAIDs (including ibuprofen) are nonselective COX inhibitors, thus contributing to gastrointestinal and renal side effects.^17–21

A relatively new group of NSAIDs that inhibit COX-2 selectively is receiving significant attention in the human literature.^22–26 As previously stated, the selective inhibition of COX-2 may be the cause of the favorable antiinflammatory, analgesic, and antipyretic effects of NSAIDs, whereas inhibition of COX-1 may result in unwarranted gastrointestinal, renal, and possibly other side effects. In humans nimesulide,²² meloxicam,^23,24 flosulide,²⁵ and etodolac²⁶ apparently produce the therapeutic effects of NSAIDs without the adverse side effects. However, it is important to note that many if not all of these NSAIDs, whether they are labeled as COX-1 or COX-2 selective, do affect both pathways in cases of excessive exposure. In fact COX selectivity appears to be species specific; etodolac is considered to be COX-2 selective in humans, but not in dogs. There is also information to suggest that many of these human-approved NSAIDs are not well metabolized at all in companion animals; information regarding metabolism and excretion of many of these drugs is not available for dogs and cats.

NSAIDs are weak acids and are well-absorbed following oral administration.^11,13 Because of their different chemical structures, differences in drug distribution and dissolution may lead to differences in the bioavailability of these drugs.^1,2 Since NSAIDs are largely ionized at physiological pH, they are primarily confined to plasma and extracellular fluid.^1,27 However, the lipid solubility of NSAIDs enhances their penetration of cell membranes, and the acidic pH of inflamed tissue draws them to target tissue.¹

Many NSAIDs are protein bound, often exceeding a rate of 99% binding to serum albumin.^1,11,12,27 Therefore the volume of distribution is small, often less than 10% of body weight. Only the unbound portion of the drug is pharmacologically active.^1,27 However, serum protein binding varies among different NSAIDs.²⁸ The rate of plasma drug clearance in small animals depends on the rate of protein binding. Plasma protein binding slows the rate of clearance.^1,27

In dogs orally administered ibuprofen is rapidly absorbed. Maximum plasma concentrations were found ½ to 3 hours after administration. Ninety-six percent of the drug is bound to serum proteins. The elimination half-life of ibuprofen in dogs ranges from 2.5 to 5.8 hours.^11,13

Clearance of NSAIDs varies among species and among individuals within species and by age.^{1,2,12,13,29–32} Very young animals (less than 6 weeks of age) and older patients metabolize these drugs more slowly and therefore have delayed clearance.¹² NSAIDs are excreted at varying rates, depending on their metabolic pathway and enterohepatic circulation.^9,11,13,32

In contrast to humans, many NSAIDs (e.g., ibuprofen, naproxen, indomethacin, piroxicam, flunixin, and tolfenamic acid) undergo enterohepatic recycling in the dog.^{2,9,11–13,32} Biliary excretion of NSAIDs allows for reabsorption and repeated exposure. In toxicity studies of ibuprofen in dogs, no metabolites of ibuprofen were demonstrated in plasma; however, high levels were demonstrated in the bile.¹³ In contrast some NSAIDs that are renally excreted in humans are excreted in the feces of dogs. This difference may partially explain the gastrointestinal sensitivities apparent in dogs compared with humans with the use of ibuprofen and other NSAIDs.^2,9,11,13

Clearance of some NSAIDs (e.g., aspirin and phenylbutazone) requires two phases of metabolism. The lipid-soluble drug, which is difficult to excrete, is metabolized to a water-soluble form that is more easily excreted. Phase I metabolism is catalyzed by enzymes in the endoplasmic reticulum in hepatocytes. These metabolites are usually more susceptible to phase II metabolism than the parent compound. A large molecule (glucuronic acid, glutathione, or sulfate) is added to the metabolite or sometimes to the parent compound. Usually this renders the drug “inactivated,” and it becomes more water-soluble and is readily excreted in the urine.^1,27 Renal elimination is pH dependent. Drug elimination usually occurs at a faster rate in alkaline urine.^1,27

Drug interactions can alter the elimination rate of NSAIDs because of changes in hepatic metabolism or renal excretion. Phenobarbital, a hepatic enzyme inducer, speeds the clearance of NSAIDs, and chloramphenicol and cimetidine, hepatic enzyme inhibitors, delay the clearance.^1,12 Drug interactions that alter renal elimination usually result when NSAIDs must compete with other weak acids for renal tubular secretory proteins. Drugs that alter urinary pH may alter renal elimination.¹ Dietary supplements and additives should be thoughtfully considered before administering NSAIDs.

Ibuprofen and other NSAIDs have the potential to cause multiorgan toxicities (Table 64-3). Adverse effects involving the gastrointestinal tract, kidneys, liver, and hematopoietic system have been documented. Risk factors that may predispose animals to side effects and drug interactions with NSAIDs exist.

Table 64-3 Adverse Reactions to NSAIDs

RISK FACTORS

A number of risk factors may predispose animals to the side effects of NSAIDs (Box 64-1). These risk factors parallel published human risk factors. They include high doses of NSAIDs, decreased renal function, gastrointestinal disease, dehydration, hypovolemia, hypotension, kidney disease, heart disease, stress, severe trauma, spinal injury, surgery or anesthesia, age, and drug interactions.*.

Additionally a possible link between NSAID therapy and acute necrotizing fasciitis was reviewed in the human literature. Group A beta-hemolytic streptococci were isolated in most of the cases associated with NSAID use. Usually the disease process developed spontaneously or after minor trauma, for which NSAIDs were prescribed for pain. The progression of the disease was quick, occurring in less than 1 week in most cases. Nearly all patients required extensive surgical debridement since in most cases intravenously administered antibiotics failed to show the progression of the disease. The authors concluded that “NSAIDs should be administered with caution, if at all, to patients with inflammatory soft-tissue lesions, especially if concurrent infection is likely.⁶²”

DRUG INTERACTIONS

NSAIDs can interact with many other drugs (Table 64-4). Clinicians should be aware of any other medications their patients are receiving. It is not uncommon for veterinarians to administer corticosteroids and NSAIDs simultaneously. Since corticosteroids have the potential to induce gastric ulcers and perforation, concurrent use with NSAIDs is likely to compound the gastrointestinal toxicity.

Table 64-4 Drug Interactions with NSAIDs

A study in canines of the use of flunixin and flunixin with prednisolone revealed endoscopically apparent gastric lesions after 4 days of flunixin therapy. Lesions occurred much earlier and were more severe in patients receiving dual medications.⁶³ Additionally, in the latter group, lesions consistent with coagulative necrosis of the superficial epithelium were found in the small intestinal and colonic mucosa. In another reported case, one dog received a different combination of NSAIDs and corticosteroids for a spinal lesion. The dog collapsed on the fourth day and was brought to the veterinarian recumbent with hemorrhagic diarrhea and tetraparesis.⁶⁴ There is no medical reason to administer corticosteroids and NSAIDs simultaneously. This practice is not without significant risk of severe consequences!

Since NSAIDs are highly protein bound, they can interact with a number of drugs, displacing other protein-bound drugs.⁶⁵ This displacement can result in increased levels of unbound drugs, which can be clinically important with drugs that have a narrow therapeutic index. Drugs of significance in this group are digoxin, oral anticoagulants, and some cytotoxic agents. NSAIDs have been shown to decrease the effectiveness of diuretics, angiotensin-converting enzyme (ACE) inhibitors, and beta-blockers.*.

CLINICAL SIGNS

The clinical signs of ibuprofen toxicosis in canines (listed in order of decreasing frequency) are vomiting, depression or stupor, diarrhea, anorexia, ataxia and incoordination, bloody stool and melena, polyuria, and polydipsia. Hemorrhagic gastroenteritis seems to develop less often in cats than in dogs, but cats may display tachypnea and panting somewhat more frequently.¹⁴

Published clinical reports show that one dog had hematemesis only.⁵ Another dog had a history of lethargy, vomiting, and anorexia for 2 weeks and was dehydrated when brought in.³ A third dog came in with a history of infrequent vomiting and melena, severe depression, anorexia, weight loss, polyuria, and polydipsia.⁶ An elevated rectal temperature, depression, and a distended abdomen are suggestive of peritonitis from a perforated gastrointestinal lesion.³ Abdominal pain was apparent in two separate canine cases of naproxen-induced gastrointestinal perforation.^66,67 Collapse and pallor may also be presenting clinical signs.

In one canine study, repeated ibuprofen administration resulted in consistent vomiting.¹¹ In another canine study of ibuprofen, gastrointestinal signs (e.g., frequent vomiting, diarrhea with the passage of fresh blood, anorexia, and weight loss) were apparent in the eighth week of dosing.¹³ In this same study, dogs given 16 mg/kg/day for 30 days showed no overt signs of toxicosis; however, postmortem examination revealed gastric erosions or ulcers and intestinal inflammation in all the dogs.¹³ These results suggest that patients with a history of NSAID administration but without clinical signs may nevertheless benefit from medical intervention.

MINIMUM DATABASE

When ibuprofen toxicosis is suspected, a complete blood count, reticulocyte count, chemistry panel, and urinalysis should be included in the diagnostic plan. Depending on the extent of the poisoning, laboratory results may be either within normal reference ranges or abnormal.

In seven canine cases with confirmed gastric ulcerations secondary to NSAID administration, all dogs had normocytic, normochromic anemias consistent with short-term blood loss.⁴⁸ A reticulocyte count was performed in six dogs, revealing a nonregenerative anemia in two and mild to moderate regeneration relative to the anemia in the other four. In a dog with peracute bleeding, the animal may be brought to the veterinarian before there is an adequate bone marrow response, and the reticulocyte count may be low. If there is prolonged bleeding, a microcytic hypochromic anemia caused by iron deficiency may be apparent.^68–70

Evaluation of serum proteins (albumin and globulin) can support a diagnosis of blood loss anemia. A decrease in both proteins occurs as a result of gastrointestinal bleeding since both proteins are lost equally.⁷⁰ Low serum proteins, however, were apparent in only three of seven dogs with confirmed NSAID-induced gastrointestinal bleeding.⁴⁸ Serum total protein concentration was normal (6.8 g/dL) in a dog with ibuprofen-induced gastric perforation.³

Leukocytosis, especially with a left shift, mandates further evaluation for the presence of a gastrointestinal perforation and peritonitis.^66,67 Serum biochemical analyses may be normal. However, results above the normal reference ranges in blood urea nitrogen (BUN), creatinine, phosphorus, and possibly calcium, plus isosthenuria, confirm a diagnosis of renal toxicosis.⁷¹

Abdominal radiographs may show no visible gastrointestinal lesions. However, in patients with gastrointestinal perforation, radiographs of the abdomen may reveal poor visualization of the serosal surfaces of the abdominal organs, free gas in the peritoneal cavity, and/or intestinal ileus.^3,66,67 If a perforation is suggested, water-soluble contrast agents should be used, since barium sulfate suspension is a complication of peritonitis that results in higher mortality.⁶⁷

Gastrointestinal imaging by ultrasound can be a quick, noninvasive way to examine the stomach and proximal duodenum.⁷² Adding water through a stomach tube can help to identify the features of gastric ulceration. These features are thickening of the gastric wall, possible loss of the normal five-layer architecture, disruption of the mucosa by crater formation, and accumulation of gas bubbles (bright echoes with typical “ring-down” or “comet-tail” gas artifacts).⁷² Additionally, abdominal ultrasound can identify fluid accumulation and may help in obtaining fluid (abdominal paracentesis) in a dog in which a perforation is suggested.⁷³ Evaluation of this fluid would reveal a purulent exudate.^3,74

Other diagnostic procedures that may be considered include coagulation profiles, platelet counts, and bleeding times. In seven dogs with confirmed NSAID-induced ulceration, coagulation profiles were normal.⁴⁸ Acquired disorders of platelet dysfunction have been attributed to NSAID use. Bleeding time can be prolonged, platelet aggregation may be poor to absent, and thrombocytopenia may be present. These effects are reversible (in contrast to those caused by aspirin) and last only as long as the NSAIDs are in circulation.⁷⁵ However, in a canine study comparing the gastroduodenal lesions that occurred after 7 days of different NSAID administration, bleeding times were normal.⁷⁶

Fecal occult blood testing can aid in the diagnosis of gastrointestinal bleeding; however, false-positive results can occur if red meat has been ingested for 3 days before testing.⁷⁷ The fecal occult blood test result was negative, however, in a canine study in which hemorrhagic gastrointestinal lesions were seen on endoscopic examination. The authors concluded that the blood loss was too small to be detected.⁷⁶