Nonsteroidal Anti-inflammatory Drugs (NSAID)
NSAID are the most commonly used class of human medications in the world. Due to their widespread availability and use, acute accidental ingestion of human NSAID in dogs and cats is quite common. Ibuprofen, aspirin, and naproxen are some of the most commonly encountered NSAID in pet animals.
NSAID inhibit the enzyme cyclooxygenase (COX; also referred to as prostaglandin synthetase), blocking the production of prostaglandins (PG). It is believed that most NSAID act through COX inhibition, although they may also have other mechanisms of action. (Also see Anti-Inflammatory Agents: Nonsteroidal Anti-inflammatory Drugs.)
Ibuprofen, 2-(4-isobutylphenyl) propionic acid, is used for its anti-inflammatory, antipyretic, and analgesic properties in animals and humans. It is rapidly absorbed orally in dogs with peak plasma concentrations seen in 30 min to 3 hr. Presence of food can delay absorption and the time to reach peak plasma concentration. The mean elimination half-life is ~4.6 hr. Ibuprofen is metabolized in the liver to several metabolites, which are mainly excreted in the urine within 24 hr. The major metabolic pathway is via conjugation with glucuronic acid, sometimes preceded by oxidation and hydroxylation.
Ibuprofen has been recommended in dogs at 5 mg/kg. However, prolonged use at this dosage may cause gastric ulcers and perforations. GI irritation or ulceration, GI hemorrhage, and renal damage are the most commonly reported toxic effects of ibuprofen ingestion in dogs. In addition, CNS depression, hypotension, ataxia, cardiac effects, and seizures can be seen. Ibuprofen has a narrow margin of safety in dogs. Dogs dosed with ibuprofen at 8–16 mg/kg/day, PO for 30 days showed gastric ulceration or erosions, along with other clinical signs of GI disturbances. An acute single ingestion of 100–125 mg/kg can lead to vomiting, diarrhea, nausea, abdominal pain, and anorexia. Renal failure may follow dosages of 175–300 mg/kg. CNS effects (ie, seizures, ataxia, depression, coma) in addition to renal and GI signs can be seen at dosages >400 mg/kg. Dosages >600 mg/kg are potentially lethal in dogs.
Cats are susceptible to ibuprofen toxicosis at approximately half the dosage required to cause toxicosis in dogs. Cats are especially sensitive because they have a limited glucuronyl-conjugating capacity. Ibuprofen toxicity is more severe in ferrets than in dogs that consume similar dosages. Typical toxic effects of ibuprofen in ferrets involve the CNS, GI, and renal systems.
Aspirin (acetylsalicylic acid), the salicylate ester of acetic acid, is the prototype of salicylate drugs. It is a weak acid derived from phenol. The oral bioavailability of aspirin may vary due to differences in drug formulation. Aspirin reduces prostaglandin and thromboxane synthesis by COX inhibition. Salicylates also uncouple mitochondrial oxidative phosphorylation and inhibit specific dehydrogenases. Platelets are incapable of synthesizing new cyclooxgenase, leading to an effect on platelet aggregation.
Aspirin is rapidly absorbed from the stomach and proximal small intestine in monogastric animals. The rate of absorption depends on gastric emptying, tablet disintegration rates, and gastric pH. Peak salicylate levels are reached 0.5–3 hr after ingestion. Topically applied salicylic acid can be absorbed systemically.
Aspirin is hydrolyzed to salicylic acid by esterases in the liver and, to a lesser extent, in the GI mucosa, plasma, RBC, and synovial fluid. Salicylic acid is 50–70% protein bound, especially to albumin. Salicylic acid readily distributes to extracellular fluids and to the kidneys, liver, lungs, and heart. Salicylic acid is eliminated by hepatic conjugation with glucuronide and glycine. Renal clearance is enhanced by an alkaline urinary pH. There are significant differences in the elimination and biotransformation of salicylates among different species. Plasma half-lives vary from 1–37.6 hr in animals.
Aspirin toxicosis is usually characterized by depression, fever, hyperpnea, seizures, respiratory alkalosis, metabolic acidosis, coma, gastric irritation or ulceration, liver necrosis, or increased bleeding time. Seizures may occur as a consequence of severe intoxication, although the exact etiology is unknown.
Cats are deficient in glucuronyl transferase and have a prolonged excretion of aspirin (the half-life in cats is 37.5 hr). No clinical signs of toxicosis occurred when cats were given 25 mg/kg of aspirin every 48 hr for up to 4 wk. Dosages of 5 grains (325 mg), bid, can be lethal to cats.
Dogs tolerate aspirin better than cats; however, prolonged use can lead to the development of gastric ulcers. Dosages of 25 mg/kg, tid, of regular aspirin have caused mucosal erosions in 50% of dogs after 2 days. Gastric ulcers were seen by day 30 in 66% of dogs given aspirin at 35 mg/kg, PO, tid. Similarly, 43% of dogs given aspirin at 50 mg/kg, PO, bid, showed gastric ulcers after 5–6 wk of dosing. Acute ingestion of 450–500 mg/kg can cause GI disturbances, hyperthermia, panting, seizures, or coma. Alkalosis due to stimulation of the respiratory center can occur early in the course of intoxication. Metabolic acidosis with an elevated anion gap usually develops later.
Naproxen, a propionic acid-derivative NSAID is available OTC as an acid or the sodium salt. It is available as 200–550 mg tablets or gelcaps or as a suspension (125 mg/5 mL). Structurally and pharmacologically, naproxen is similar to carprofen and ibuprofen. In humans and dogs, it is used for its anti-inflammatory, analgesic, and antipyretic properties.
Oral absorption of naproxen in dogs is rapid, with peak plasma concentration reached in 0.5–3 hr. The reported elimination half-life in dogs is 34–72 hr. Naproxen is highly protein bound (>99.0%). In dogs, naproxen is primarily eliminated through the bile, whereas in other species, the primary route of elimination is through the kidneys. The long half-life of naproxen in dogs appears to be due to its extensive enterohepatic recirculation.
Several cases of naproxen toxicosis in dogs have been described. Dosages of 5.6–11.1 mg/kg, PO, for 3–7 days have caused melena, frequent vomiting, abdominal pain, perforating duodenal ulcer, weakness, stumbling, pale mucous membranes, regenerative anemia, neutrophilia with a left shift, increased BUN and creatinine, and decreased total protein. Acute toxicity from a single oral dose has been described at 35 mg/kg. Cats may be more sensitive to naproxen toxicity than dogs due to their limited glucuronyl-conjugating capacity.
Treatment of NSAID toxicosis consists of early decontamination, protection of the GI tract and kidneys, and supportive care. Vomiting should be induced in recent exposures, followed by administration of activated charcoal with a cathartic. Activated charcoal can be repeated in 6–8 hr to prevent NSAID reabsorption from enterohepatic recirculation. Use of H2-receptor antagonists (ranitidine, famotidine, cimetidine) may not prevent GI ulcers but can be useful in treating them. Omeprazole, which is a proton pump inhibitor used for inhibiting gastric acid secretions, can be used instead of an H2-blocker at 0.5–1.0 mg/kg, PO, sid, in dogs. Sucralfate (dog: 0.5–1 g, PO, bid-tid; cat: 0.25–0.5 tablet, PO, bid-tid) reacts with hydrochloric acid in the stomach and forms a paste-like complex that binds to the proteins in ulcers and protects them from further damage. Because sucralfate requires an acidic environment, it should be given ≥30 min before administering H2 antagonists. Misoprostol (dog: 1–3 μg/kg, PO, tid) has recently been shown to prevent GI ulceration when used concomitantly with aspirin and other NSAID.
IV fluids should be given at a diuretic rate if the potential for renal damage exists. Alkalinization of the urine with sodium bicarbonate results in ion trapping of salicylates in kidney tubules and can increase their excretion. However, ion trapping should be used judiciously and only in cases where the acid-base balance can be monitored closely. Baseline renal function should be monitored and rechecked at 24, 48, and 72 hr. Prognosis depends on the dose ingested and how soon the animal receives treatment following exposure.
Acetaminophen is a synthetic nonopiate derivative of p-aminophenol widely used in humans for its antipyretic and analgesic properties. Its use has largely replaced salicylates due to the reduced risk of gastric ulceration.
Acetaminophen is rapidly absorbed from the GI tract. Peak plasma concentrations are usually seen within an hour, but can be delayed with extended-release formulations. It is uniformly distributed into most body tissues. Protein binding varies from 5–20%. The metabolism of acetaminophen involves 2 major conjugation pathways in most species. Both involve cytochrome P450 metabolism, followed by glucuronidation or sulfation.
Cats are more sensitive to acetaminophen toxicosis because they are deficient in glucuronyl transferase and therefore have limited capacity to glucuronidate this drug. In cats, acetaminophen is primarily metabolized via sulfation; when this pathway is saturated, toxic metabolites are produced. In dogs, signs of acute toxicity are usually not observed unless the dosage of acetaminophen exceeds 100 mg/kg. Clinical signs of methemoglobinemia have been reported in 3 out of 4 dogs at 200 mg/kg. Toxicity can be seen at lower dosages with repeated exposures. In cats, toxicity can occur with 10–40 mg/kg.
Methemoglobinemia and hepatotoxicity characterize acetaminophen toxicosis. Renal injury is also possible. Acute keratoconjunctivitis sicca has been reported in some dogs following acetaminophen ingestion. Cats primarily develop methemoglobinemia within a few hours, followed by Heinz body formation. Methemoglobinemia makes mucous membranes brown or muddy in color, and is usually accompanied by tachycardia, hyperpnea, weakness, and lethargy. Other clinical signs of acetaminophen toxicity include depression, weakness, hyperventilation, icterus, vomiting, hypothermia, facial or paw edema, cyanosis, dyspnea, hepatic necrosis, and death. Liver necrosis is more common in dogs than in cats. Liver damage in dogs is usually seen 24–36 hr after ingestion. Centrilobular necrosis is the most common form of hepatic necrosis seen with acetaminophen toxicity.
The objectives of treating acetaminophen toxicosis are early decontamination, prevention or treatment of methemoglobinemia and hepatic damage, and provision of supportive care. A Schirmer tear test (to confirm keratoconjunctivitis) can be used if necessary. Induction of emesis is useful when performed early. This should be followed by administration of activated charcoal with a cathartic. Activated charcoal may be repeated because acetaminophen undergoes some enterohepatic recirculation.
Administration of N-acetylcysteine (NAC), a sulfur-containing amino acid, can reduce the extent of liver injury or methemoglobinemia. NAC provides sulf-hydryl groups, directly binds with acetaminophen metabolites to enhance their elimination, and serves as a glutathione precursor. It is available as a 10% or 20% solution. The loading dose is 140 mg/kg of a 5% solution IV or PO (diluted in 5% dextrose or sterile water), followed by 70 mg/kg, PO, qid for generally 7 or more treatments (some authors recommend up to 17 doses). Vomiting can occur with oral NAC. NAC is not labeled for IV use; however, it can be administered as a slow IV (over 15–20 min) with a 0.2 micron bacteriostatic filter. Activated charcoal and oral NAC should be administered 2 hr apart as activated charcoal could adsorb NAC.
Liver enzymes should be monitored and rechecked at 24 and 48 hr. The animal should also be monitored for methemoglobinemia, Heinz body anemia, and hemolysis. Fluids and blood transfusions should be given as needed. Ascorbic acid (30 mg/kg, PO or injectable, bid-qid) may further reduce methemoglobin levels. Cimetidine (5–10 mg/kg, PO, IM, or IV), a cytochrome P450 inhibitor, may help reduce formation of toxic metabolites and prevent liver damage. S-Adenosyl methionine has been suggested as an adjunct for managing acute or chronic hepatic injury at 18 mg/kg, PO, for 1–3 mo in dogs and cats.
Last full review/revision March 2012 by Safdar A. Khan, DVM, MS, PhD, DABVT