Ibuprofen Toxicosis in Dogs, Cats, and Ferrets Eric Dunayer, MS, VMD
Total Page：16
File Type：pdf, Size：1020Kb
Toxicology Brief managing common poisonings in companion animals PEER-REVIEWED Ibuprofen toxicosis in dogs, cats, and ferrets Eric Dunayer, MS, VMD nonsteroidal anti-inflammatory drug (NSAID) de- rived from propionic acid, ibuprofen has analgesic, A anti-inflammatory, and antipyretic effects. It is com- monly used in humans for short-term management of pain and fever and for long-term control of arthritic pain. It comes in various strengths. For over-the-counter use, it is available in 50- and 100-mg capsules or tablets (often chewable) and 20- and 40-mg/ml liquids for children, and in 200-mg tablets and capsules for adults. Prescription-strength tablets are 400, 600, and 800 mg. Ibuprofen also can be found combined with other medications such as pseudoephedrine hydrochlo- ride or hydrocodone bitartrate. Common brand names of ibuprofen preparations include Advil (Wyeth), Midol (Bayer HealthCare), and Motrin (McNeil Consumer), although ibuprofen also is available in many generic formulations.1 In humans, ibuprofen taken at standard dosages appears to have a wide margin of safety. In general, there are fewer side effects than with similarly dosed aspirin.1 However, in hibits the conversion of arachidonic acid into various pros- dogs, cats, and ferrets, ibuprofen has a narrow margin of taglandins by reversibly blocking the actions of cyclooxyge- safety and is a frequent toxicosis reported to the ASPCA Ani- nase (COX) enzymes. By inhibiting COX-2 enzymes, ibupro- mal Poison Control Center (APCC). In one review of ASPCA fen reduces the production of inflammatory mediators such 3 APCC data on calls reporting generic drug exposures in dogs as prostaglandin E2 (PGE2 ) and prostaglandin F2α (PGF2α ). and cats, ibuprofen was the most common drug involved.2 However, ibuprofen also inhibits COX-1 enzymes, which Dogs were the animals most commonly poisoned by ibupro- can reduce the production of substances necessary for fen, and most exposures were acute—usually the result of maintaining the normal gastric mucosal barriers, renal ingestion of numerous tablets after a dog chewed open a blood flow, and platelet aggregation.1 bottle (ASPCA APCC Database: Unpublished data, 2001–2003). Some ibuprofen formulations have a sweet coating and are Pharmacokinetics readily eaten by dogs. In some cases, ibuprofen was admin- istered to pets in the mistaken belief that it was safer than as- About 80% of ibuprofen is absorbed when taken orally in pirin (ASPCA APCC Database: Unpublished data, 2001–2003). humans1; in dogs, 60% to 86% of the dose is absorbed.4 In humans, the time to reach peak plasma concentrations varies from 47 to 120 minutes, depending on the formulation. Liq- Mechanism of action uid forms reach peak concentrations soonest, chewables While the exact mechanism of ibuprofen’s action is not next, and tablets last. Ingesting ibuprofen with food de- fully understood, it is generally thought that ibuprofen in- creases the peak plasma concentration and increases the time to reach it.1 Ibuprofen is highly protein-bound (90% to 99%).1 Elimina- “Toxicology Brief” was contributed by Eric Dunayer, MS, VMD, ASPCA Animal Poison Control Center, 1717 S. Philo Road, Suite 36, Urbana, IL tion is through hepatic biotransformation to inactive metabo- 61802. The department editor is Petra A. Volmer, DVM, MS, DABVT, DABT, lites excreted by kidney filtration and secretion. About 70% of College of Veterinary Medicine, University of Illinois, Urbana, IL 61802. the drug is excreted in the urine as metabolites or unchanged drug; the rest is lost through feces. Marked enterohepatic re- 580 JULY 2004 Veterinary Medicine Toxicology Brief continued TABLE 1 Ibuprofen Dose and Associated Signs or Outcomes in Dogs* Dose Associated Signs or Outcomes 25–125 mg/kg Vomiting, diarrhea, nausea, abdominal pain, anorexia > 175 mg/kg All of the above plus hematemesis, melena, polyuria or polydipsia, oliguria, uremia, acute renal failure > 400 mg/kg All of the above plus seizures, ataxia, coma, shock > 600 mg/kg Death *Source: Adapted from Villar, D. et al.: Ibuprofen, aspirin and acetaminophen toxicosis and treatment in dogs and cats. Vet. Hum. Toxicol. 40 (3):156–161; 199; and the ASPCA APCC Database: Unpublished data, 2001–2003. circulation occurs.5 In dogs, the elimi- nal pain, hematemesis, and diarrhea nation half-life is 3.9 to 5.3 hours.4 can be seen within 24 hours of inges- tion.10 Single, acute overdoses as low as 25 mg/kg can cause vomiting in Toxicity dogs (ASPCA APCC Database: Unpub- Ibuprofen has a narrow margin of lished data, 2003). safety in dogs. One recommended At doses greater than 175 mg/kg, dosage is 5 mg/kg/day, divided.3 How- the risk of acute renal failure in dogs ever, signs of toxicosis have been seen increases. In the kidney, prostaglan- with a dosage of 8 mg/kg/day for 30 dins are responsible for vasodilation days. At this dosage, no clinical signs and maintenance of the renal were seen, but the dogs developed gas- medulla’s blood flow, especially dur- tric ulcers and intestinal inflammation.6 ing hypovolemic states. Ibuprofen At 16 mg/kg/day, vomiting, diarrhea, blocks these vasodilatory prostaglan- melena, and weight loss were evident dins. The resultant diminished renal by the eighth week of administration.6 blood flow can lead to acute interstitial In one case report, a dog given 3 nephritis, papillary necrosis, renal- mg/kg every other day for six weeks tubular necrosis, and acute renal fail- developed a fatal gastric perforation.7 ure. Preexisting renal disease, hypo- Renal insufficiency or failure, impaired volemia (possibly from vomiting and hepatic function, hypoalbuminemia, concurrent dehydration), and hypoten- stress (such as recent surgery), or con- sion can increase the risk of renal toxi- current administration of glucocorti- city from ibuprofen.3 coids may increase the toxicity of At doses greater than 400 mg/kg, ibuprofen administered long-term.7,8 central nervous system effects can be An acute ibuprofen overdose in seen in dogs, including depression, dogs, cats, ferrets, and humans is as- seizures, and coma.11 The mechanism sociated with gastrointestinal, renal, for these signs is unknown. The mini- and central nervous system signs. Gas- mum lethal dose in dogs is about 600 trointestinal signs are thought to be mg/kg.11 In addition, hepatotoxicity due to the inhibition of COX-1 en- (especially with long-term use) and in- zymes and the loss of normal gastric hibition of platelet function have been protective mechanisms, though this reported in humans.5 may be an oversimplified explanation Table 1 shows signs associated with of the mechanism.9 Vomiting, abdomi- increasing doses of ibuprofen in dogs. ➤ 582 JULY 2004 Veterinary Medicine Toxicology Brief continued Cats, because of limited glucuronyl- chronic exposure. For possible gas- conjugating ability, are thought to be trointestinal upset and ulceration, use twice as sensitive as dogs to ibupro- gastrointestinal protectants. For inges- fen’s toxic effects.10 tion of low doses of ibuprofen (< 100 Ferrets are especially sensitive to mg/kg), over-the-counter liquid ant- ibuprofen’s toxic effects. Because of acids containing aluminum or magne- their small size (an adult weight of 0.5 sium hydroxide can be used.11 Do not to 2 kg),12 ingestion of a single 200- use agents that contain bismuth sub- mg tablet can result in a dose of 100 salicylate (such as Pepto-Bismol [Proc- to 400 mg/kg. In one review of cases ter & Gamble] and newer formulations received by the ASPCA APCC, 93% of of Kaopectate [Pfizer]) because of the possible interaction of salicy- lates with the ibuprofen. For Administer multiple ingestion of higher doses or when gastrointestinal signs doses of activated have occurred, a combina- charcoal in all tion therapy of acid reducers (H2-blockers or proton- affected animals. pump inhibitors), sucralfate (liquid or a slurry of tablets), ferrets ingesting ibuprofen developed and misoprostol may be used (Table neurologic signs, including depres- 2). Continue treatment for seven to 14 sion, coma, and ataxia. Slightly more days or more, depending on the dose than half the ferrets developed vomit- and clinical signs. Control vomiting ing or diarrhea. The minimum lethal with an appropriate antiemetic. If gas- dose in ferrets was about 220 mg/kg.13 trointestinal bleeding is severe, trans- fusions may be necessary. Treat gas- trointestinal perforation surgically.10,11 Treatment At doses that may cause renal fail- After an acute ibuprofen overdose, ure, diuresis with intravenous fluids rapid and aggressive decontamina- given at twice the daily maintenance tion, as with most toxicants, is im- rate (120 ml/kg/day) for at least 48 portant.2 In clinically normal animals hours is recommended. Obtain base- (i.e. those not vomiting or showing line blood urea nitrogen, creatinine, neurologic signs), attempt emesis, and phosphorus concentrations, and especially within two hours of the recheck them daily. Serial urinalysis ingestion. In animals exhibiting neu- can be used to monitor for tubular rologic signs and not, therefore, can- casts, which may be seen in as little as didates for emesis, gastric lavage or 18 hours. If renal function test results enterogastric lavage may be useful. are normal at 48 hours, reduce fluid Administer multiple doses of acti- therapy to maintenance rates, and then vated charcoal (every six to eight discontinue it in 24 hours if renal val- hours for 24 hours) in all affected ues remain normal. If the test results animals because ibuprofen under- are elevated, continue diuresis until goes enterohepatic recirculation.10,11 the values normalize or stabilize.10,11 Other treatments should be di- Treat neurologic signs sympto- rected at preventing or treating possi- matically. Control seizures with di- ble complications of either acute or azepam or barbiturates as needed. ➤ 584 JULY 2004 Veterinary Medicine Toxicology Brief continued TABLE 2 Drugs Used to Protect the Gastrointestinal Tract in Ibuprofen Toxicosis* Drug Dosage** Acid Reducers Famotidine 0.5–1 mg/kg PO, SQ, IM, IV b.i.d.