CHAPTER 76 NONSTEROIDAL ANTIINFLAMMATORY DRUGS Sarah Haldane,
BVSc, BAnSc, MANZCVSc, DACVECC
KEY POINTS • The incidence of adverse drug events caused by NSAIDs is high. • Despite their increased safety margin, adverse gastrointestinal effects are still the most common side effects of COX-2–selective NSAIDs. • The toxic dose of an NSAID can vary with the chronicity of administration as well as the patient’s age, comorbidity, and concurrent medications. • Overdose of NSAIDs should be treated as an emergency even if the patient is not yet showing clinical signs of toxicity. • Client education plays a key role in reducing the risk and improving the outcome of NSAID toxicity.
Nonsteroidal antiinflammatory drugs (NSAIDs) are among the most commonly used medications in human and veterinary medicine. The potential for small animals to develop toxicoses is enormous because the drugs are encountered frequently in household medicine cabinets, and many of the NSAIDs have a small therapeutic margin for safety. The incidence of adverse drug events associated with NSAIDs is high in veterinary patients; they are among the most common medication-related calls to poison control centers and to the U.S. Federal Drug Administration’s Center for Veterinary Medicine.1,2
COX-1, COX-2, AND PROSTAGLANDINS After a tissue has been damaged, arachidonic acid is released from cell membranes, precipitating a chain of events known as the arachidonic acid cascade. Two enzyme groups metabolize arachidonic acid: the lipoxygenases (LOX) and the cyclooxygenases (COX). Products from the LOX cascade include leukotrienes and chemotactic factors. Products of the COX cascade include prostacyclin, thromboxanes, and prostaglandins. Prostaglandins have diverse effects in many organ systems. They are often important in maintaining local blood supply to tissues. Continuously produced (constitutive) prostaglandins are required for the normal function of the brain, kidneys, gastrointestinal tract, primary hemostatic system, and reproductive system. Inducible prostaglandins are produced in response to tissue injury. They escalate the inflammatory response and increase peripheral nerve sensitization; they also have protective actions and play a role in tissue repair.3,4 The two main COX enzymes are known as COX-1 and COX-2. Although most COX-1–induced prostaglandins are constitutive and have homeostatic effects, some are also produced in response to tissue injury. Similarly, although many prostaglandins produced by COX-2 are inducible, there are constitutive COX-2 prostaglandins found in the brain, intestine, and kidneys in many species.4-7 NSAIDs are potent inhibitors of prostaglandin production. They are described as being nonspecific or dual acting if they inhibit both COX-1 and COX-2. Aspirin is the classic example of a dual-acting NSAID. Other examples in the veterinary market include ketoprofen
and tepoxalin. COX-2–selective drugs have also been produced. The purpose of these drugs is to reduce inflammatory prostaglandin production via COX-2 inhibition with relatively less suppression of COX-1. However, all COX-2 inhibitors still inhibit COX-1 to some degree. A number of veterinary COX-2–selective NSAIDs are available, including carprofen, meloxicam, deracoxib, and firocoxib. A COX variant, known as COX-3, has been isolated in the dog’s brain and has similar inflammatory and pyretic effects to COX-1 and COX-2. Acetaminophen has been shown to specifically inhibit COX-3, so it has antiinflammatory and antipyretic effects in the brain. COX-3 in other species does not have the same inflammatory effects as in dogs.8,9 Older-generation NSAIDs, such as ibuprofen and naproxen, are far more likely to cause adverse effects than the newer formulations; however, the potential for complications still exists with chronic use or overdose of COX-2–selective NSAIDs. NSAID administration can have significant detrimental effects in animals with fluid deficits, gastrointestinal, renal, or hepatic disease or with disorders of primary coagulation.
POTENTIAL ADVERSE EFFECTS Gastrointestinal Effects Gastric ulceration is a common side effect of NSAID administration with prolonged use, high doses, or administration to hypovolemic or inappetent animals.10,11 COX-1–induced prostaglandins in the gastric mucosa have protective effects: they increase gastric mucous production and enhance local blood flow. COX-2 is stimulated once damage has occurred to the intestinal mucosa and produces prostaglandins that play an important role in mucosal healing.3,6,11-13 This means that NSAID administration can cause gastric ulceration and inhibit the ability of ulcers to heal. Some NSAIDs, such as aspirin, can cause direct injury to the gastric mucosa by disrupting surface phospholipids, allowing gastric acid to penetrate directly to the cells in the wall of the stomach.6,14 In addition to their mucosal effects, COX-1– and COX-2–induced prostaglandins are important in the regulation of gastrointestinal motility.15,16 Despite their increased safety margin, adverse gastrointestinal effects are still the most common side effects of COX-2–selective NSAIDs.10,11 NSAIDs are weak acids that become lipid soluble in the highly acidic environment in the stomach. This allows them to penetrate easily into gastric cells, where they become trapped in the relatively more alkaline environment. This leads to a high local concentration of NSAIDs in the gastric mucosa and may be an explanation for adverse effects occurring in the gastrointestinal system at lower doses than in other organ systems.2 In one experimental study assessing long-term NSAID use in dogs, carprofen had the lowest incidence of gastrointestinal side effects when compared with meloxicam, ketoprofen, flunixin meglumine, and etodolac.17 Multiple endoscopic and mucosal permeability studies have been performed evaluating the effects of short-term NSAID use, and no significant adverse effects have been found. However, because of the nature of 395
PART VIII • THERAPEUTIC DRUG OVERDOSE
these studies, only a few dogs were assessed in each, making it difficult to evaluate the importance of their findings.14,18-22 Deracoxib, meloxicam, and carprofen have been associated with gastrointestinal perforation. In most of these cases the drugs were administered at higher-than-recommended dosages or were administered concurrently with a corticosteroid or another NSAID.23-28
Renal Effects When perfusion to the kidney declines, glomerular filtration rate (GFR) decreases accordingly. The juxtaglomerular apparatus (JGA) in the kidney releases prostaglandins that vasodilate the afferent renal arteriole to maintain renal blood flow and GFR. They also stimulate the release of renin from the JGA. This effect is mediated by the COX-1 and COX-2 enzymes.29 When NSAIDs are administered to a hypovolemic patient, the prostaglandin-mediated effect of local vasodilation is diminished or lost. Significant damage to the kidneys can result and this can lead to acute renal failure.7 Also, COX-2–selective medications can increase the relative production of thromboxanes, which have local vasoconstrictive effects and can exacerbate renal damage. Ketoprofen, carprofen, and tepoxalin at therapeutic doses have been shown to have little effect on renal perfusion in healthy anesthetized dogs. However, overdose or accidental ingestion of large doses of NSAIDs can potentially lead to acute renal failure despite normal blood volume.7,10
Hepatic Effects NSAIDs are metabolized in the liver, primarily by conjugation with glycin or glucuronic acid. NSAID use has been associated with an increase in liver enzymes and hepatocellular injury in some patients. This toxicity does not depend on dose or duration of treatment and therefore is classified as an idiosyncratic reaction. In one report describing hepatoxicity secondary to carprofen administration, there was a marked similarity in the course of disease among Labrador Retrievers, which may indicate a possible underlying genetic basis in this breed. However, this result may have been influenced by the large number of Labradors that require NSAID administration for degenerative joint disease.30 Because of the risk of hepatic toxicity, NSAID administration is not recommended for animals with concurrent liver disease.
Coagulation Effects Prostacyclin (PGI2) is produced from epithelial cells via COX-2 synthesis and inhibits platelet aggregation and causes vasodilation. COX-1 mediates production of thromboxane A2 (TXA2) from platelets, which increases platelet aggregation and causes vasoconstriction.31 The balance between TXA2 and PGI2 is important in maintaining a functional coagulation system. Aspirin is the most effective NSAID for reducing platelet aggregation because it binds permanently and decreases TXA2 production for the life of the platelet. Conversely the COX-2–selective coxib class of drugs has been associated with increased risk of thrombosisrelated cardiac events in humans.32 In veterinary medicine, ketoprofen, carprofen, tepoxalin, meloxicam, and deracoxib have been studied to assess their affects on primary hemostasis. Ketoprofen and carprofen have been associated with decreased platelet function and deracoxib with potential for increased thrombosis in experimental trials; however, there are no published reports of clinically relevant hemostatic complications in dogs or cats.17,31,33,34
Bone and Cartilage Effects Studies in animal models have shown that aspirin, indomethacin, and naproxen can have a deleterious effect on cartilage formation, which is significant because NSAIDs are often the primary therapeutic agents used to manage osteoarthritis in dogs and cats.35-37 In
contrast, in vitro studies have been performed showing that COX-2– selective NSAIDs may have a protective effect on human chondrocytes in early osteoarthritis.38 In dogs, carprofen has been shown to reduce the severity of early structural changes and histologic lesions in experimental models of osteoarthritis.39,40 Rofecoxib had a protective effect on cartilage in experimental trials in rats, and meloxicam did not cause further cartilage damage in a trial of calcium pyrophosphate crystal–induced osteoarthritis in dogs.37,41 Potential effects of NSAIDs on the rate of bone healing are also a concern. Long-term carprofen administration may reduce bone healing after fracture, and meloxicam has also been shown to reduce fracture healing in a mouse model.42,43 In general, experimental trial results vary, and outcomes differ based on the type, dose, and duration of the NSAID given to the subject as well as the species of the subject. Controversy remains regarding the impact of long-term NSAID use in osteoarthritis and bone healing, and further in vivo studies and clinical trials are necessary.36
Neurologic Effects The most common adverse effect of NSAIDs in the central nervous system (CNS) of people is aseptic meningitis. A number of drugs have been reported to cause this, including meloxicam, diclofenac, naproxen, and ibuprofen.44-47 There are no published cases of neurologic side effects of NSAID administration in veterinary medicine; however, anecdotal reports suggest that high doses of ibuprofen can cause seizures in dogs.48
DRUG INTERACTIONS WITH NSAIDs Concurrent administration of two NSAIDs or an NSAID with a corticosteroid significantly increases the risk of gastrointestinal and renal injury and can impede healing of ulcers.10,13,14,26,49 Aspirin in particular increases the risk of GI bleeding when administered with other NSAIDs or corticosteroids.6,11,49 NSAIDs are highly protein bound in the plasma and displace other protein-bound drugs, increasing their bioavailability and potentially leading to toxic plasma concentrations. These drugs include other antiinflammatory agents, warfarin, phenytoin, penicillins, and sulfonamide antibiotics. NSAIDs can also increase plasma levels of digoxin and can decrease the efficacy of furosemide. Use of NSAIDs with other potentially nephrotoxic drugs, such as aminoglycoside antibiotics, is relatively contraindicated, but studies have not been performed to prove a clinical interaction. Diuretic use is not recommended in conjunction with NSAIDs because of the risk of hypovolemia and subsequent renal toxicity.7 Drugs that induce cytochrome P450 metabolic pathway in the liver (e.g., phenobarbitone) can increase NSAID metabolism, reducing their analgesic efficacy.
TOXIC DOSAGE The toxic dose of individual NSAIDs can be difficult to determine: it depends on the nature of the ingestion (i.e., acute or chronic), the species and age of the patient, the patient’s morbidity, and the administration of any concurrent medications. Furthermore, individual animals vary with regard to the length of time it takes to metabolize some of the NSAIDs, particularly ibuprofen, aspirin, deracoxib, and carprofen.50-54 Even therapeutic doses of NSAIDs can have adverse effects in any patient with concurrent illness. Some of the NSAIDs have been studied to determine an acute toxic dose. These doses must be interpreted with care because they were generally extrapolated from only a small number of cases. In one report in dogs, ibuprofen doses of 100 mg/kg caused clinical
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signs of gastrointestinal disease, whereas renal failure occurred at a dose of 175 mg/kg. In this study, 600 mg/kg of ibuprofen caused acute death.55 However, ibuprofen at only 8 mg/kg/day has been reported to cause gastrointestinal ulceration after 30 days of therapy.56 Cats can show adverse effects of ibuprofen administration at approximately half the dose of dogs because of their limited ability to metabolize the drug through glucuronidation.57 Aspirin can cause gastrointestinal erosions in dogs at doses of 75 mg/kg/day after 2 days. Acute ingestion of 400 mg/kg can cause toxicity in dogs.55 In cats, 25 to 100 mg/kg/day can cause gastric ulceration.58 Doses as low as 5 to 10 mg/kg of naproxen have been reported to cause adverse effects in dogs59,60 as have doses of greater than 6 mg/kg of deracoxib.61 Meloxicam can cause gastrointestinal upset in dogs at 0.15 to 0.2 mg/kg/day for 3 days.36,62 Renal failure has been reported in dogs after 3 days of therapy at 0.6 to 1 mg/kg/day.62
CLINICAL SIGNS The clinical signs associated with gastrointestinal toxicity of NSAIDs are often nonspecific and include inappetence, lethargy, and vomiting. Depending on the location of the mucosal injury, hematemesis, melena, or hematochezia can occur. These signs are seen less commonly in cats with gastrointestinal ulceration than with dogs.25 Intestinal perforation can cause chemical or septic peritonitis. Signs may include acute pain, hypovolemia, and, in some cases, fever. Animals may be presented in a collapsed state as a result of hypovolemic or septic shock. Renal injury can result in polyuria or oliguria, dehydration, inappetence, abdominal pain, and vomiting. If NSAIDs cause a clinical coagulopathy, signs of bleeding from mucosal surfaces could be observed, including epistaxis, hematemesis, or melena.
DIAGNOSIS OF NSAID TOXICITY In most cases NSAID toxicosis is diagnosed by the presence of relevant clinical signs associated with a history of NSAID use. In cases of accidental overdose, patients can be presented before the onset of clinical signs and the diagnosis is based on history alone. The emergency database may show alterations in acid base and electrolyte concentrations. The most common acid base abnormality seen is metabolic acidosis; however, patients that have vomited a significant volume of gastric fluid can present with a metabolic alkalosis. Vomiting, diarrhea, hypovolemia, and potential renal losses can affect electrolyte concentrations; therefore sodium, potassium, and chloride concentrations can be variable, depending on the location of injury and severity of illness in individual patients. A hemogram may indicate anemia in patients with gastrointestinal hemorrhage or coagulopathy. Conversely, an increase in packed cell volume and plasma protein concentration is seen in dehydrated animals. There may be leukocytosis if there is gastroenteritis or peritonitis. The platelet count is unlikely to be decreased significantly, even in coagulopathy, because NSAIDs affect the function but not the number of platelets. A buccal mucosal bleeding time can be used to assess platelet function. Coagulation tests, such as prothromin time (PT) and activated partial thromboplastin time (aPTT), can be performed to rule out other causes of coagulopathy; these tests are not affected by NSAID toxicity. Biochemistry results may show evidence of azotemia that can be prerenal because of dehydration or renal if the patient is in acute renal failure. A patient with gastrointestinal hemorrhage may have an increase in blood urea nitrogen without a concurrent increase in creatinine, indicating digestion of blood. Hepatic toxicity causes an increase in alanine transferase, alkaline phosphatase, and, less frequently, serum bilirubin.
Urinalysis can be used to determine whether renal damage is present and to differentiate between renal and prerenal azotemia. Isosthenuria can be indicative of acute renal insufficiency. NSAIDs cause renal tubular injury, so an early sign of toxicity is the presence of casts in the urine sediment. Proteinuria may be present in cases of glomerular damage secondary to reduced renal perfusion. In some cases abdominal imaging is indicated to rule out other causes of gastrointestinal injury or to find evidence of peritonitis, such as free fluid or air in the peritoneal cavity. If free fluid is present, abdominocentesis is indicated, and the fluid’s glucose, lactate, protein, and cell count and differential should be examined (see Chapter 200).
TREATMENT Asymptomatic Patients Asymptomatic patients that are presented after accidental overdose should be treated prophylactically to prevent renal and gastrointestinal injury. Induction of emesis may be beneficial in cases that are presented within 2 to 4 hours of ingestion. Activated charcoal can be administered to adsorb any medication that still is present within the GI tract. Many NSAIDs undergo enterohepatic recycling, so repeated dosing of activated charcoal every 4 to 6 hours is recommended (see Chapters 74 and 76). Intravenous fluid therapy is vital to maintain perfusion to the gastrointestinal tract and kidneys. In most cases of medication overdose, treatment duration depends on the half-life of the drug that has been ingested; treatment should continue until at least three halflives have passed (Table 76-1). However, NSAIDs can have a longer half-life in the tissues than in the plasma, so treatment should continue if there is laboratory evidence of abnormality or if clinical signs develop.63 Urine sediment should be monitored daily, even in asymptomatic animals, to look for evidence of renal casts. Gastrointestinal protectants are indicated to prevent or treat gastric mucosal injury. Proton pump inhibitors such as omeprazole and pantoprazole are more effective at increasing gastric pH than the histamine-2 receptor antagonists ranitidine and famotidine; however, the proton pump inhibitors have a longer onset of action. Misoprostol is a prostaglandin E2 analog and can be used to counteract the effects of NSAIDs.64 Oral medications should not be administered while the patient is receiving activated charcoal because the medications will also be adsorbed.
Symptomatic Patients If patients are showing clinical signs of NSAID toxicity, then decontamination procedures such as emesis or activated charcoal are not beneficial because the medication will already have been absorbed
Table 76-1 Elimination Half-Life of Nonsteroidal Antiinflammatory Drugs in Dogs and Cats Drug
37.5 hr* (up to 45 hr) 54
21 hr (up to 49 hr)52
24 hr72 (up to 36 hr)
12 hr71 15-26 hr73
*Half-life is dose dependent and increases with higher or prolonged dosing.
PART VIII • THERAPEUTIC DRUG OVERDOSE
from the gastrointestinal tract. Intravenous fluid therapy is required to treat initial perfusion deficits and dehydration and should be continued to ensure adequate blood flow to the GI tract and kidneys. Symptomatic treatment of nausea, vomiting, and pain is warranted if these signs are present. Metoclopramide should be avoided because this dopamine antagonist could decrease renal blood flow.65,66 Gastric protectant drugs and appropriate use of nutrition can be used to accelerate healing and improve function of the gastrointestinal tract. Patients with septic peritonitis or acute renal failure should be treated appropriately (see Chapter 122). Patients with significant gastrointestinal hemorrhage may require a blood transfusion if the patient is showing clinical signs of anemia. Treatment of platelet abnormalities with platelet products is rarely, if ever, indicated in NSAID toxicity.
PROGNOSIS The prognosis for patients with NSAID toxicity depends on the organ system affected, how early the toxicity is detected, and the severity of organ injury. The degree of organ injury is generally dose related but can also be affected by age, comorbidity, and concurrent medications. The majority of data in the veterinary literature relates to gastrointestinal injury secondary to NSAID administration. In most cases the prognosis is good for patients with gastrointestinal ulceration or hemorrhage, given appropriate treatment and withdrawal of the NSAID. However, although in some reports patients made a good recovery after surgical repair and appropriate treatment, more than 50% of the published cases of NSAID-induced gastrointestinal perforation died or were euthanized because of the severity of disease or cost of treatment.23-27
CLIENT EDUCATION The relative frequency of NSAID toxicoses in veterinary patients means that client education is vital. If NSAIDs are prescribed for home administration, the dose and duration of treatment must be explained carefully and the potential side effects of the medication described clearly. Clients should be advised not to administer the medications and to seek veterinary advice if their pet is not eating, is vomiting or has diarrhea, or if they see hematochezia or melena. NSAIDs should never be administered concurrently with other NSAIDs or with corticosteroids. When using NSAIDs as long-term therapy, clinicians may find that they can titrate the dose over time to the lowest therapeutic dose. Many NSAIDs have been shown to be effective analgesics and antiinflammatory agents at amounts far lower than the recommended dose, but this may depend on the individual patient.67-69
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