Nonsteroidal Anti-inflammatory Drugs
NSAIDs are the most commonly used class of human
medications in the world. Because of their widespread availability and use,
acute accidental ingestion of human NSAIDs in dogs and cats is quite common.
Ibuprofen, aspirin, and naproxen are some of the most commonly encountered
NSAIDs in pet animals.
NSAIDs inhibit the enzyme cyclooxygenase (COX; also
referred to as prostaglandin synthetase), blocking the production of
prostaglandins. It is believed that most NSAIDs act through COX inhibition,
although they may also have other mechanisms of action. (Also see Nonsteroidal Anti-inflammatory Drugs.)
Ibuprofen, 2-(4-isobutylphenyl) propionic acid, is used for its
anti-inflammatory, antipyretic, and analgesic properties in animals and people.
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
Cats are susceptible to ibuprofen toxicosis at
approximately half the dosage required to cause toxicosis in dogs. Cats are
especially sensitive, because they have 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
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 because of 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, RBCs, 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
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
cause is unknown.
Cats are deficient in glucuronyl transferase and have a
prolonged excretion of aspirin (half-life 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 development of gastric ulcers. Regular aspirin at dosages of 25
mg/kg, tid, has 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 increased anion gap usually develops
Naproxen, a propionic acid-derivative NSAID, is available OTC as an
acid or the sodium salt. It is available as tablets or gelcaps (200–550 mg) or
as a suspension (125 mg/5 mL). Structurally and pharmacologically, naproxen is
similar to carprofen and ibuprofen. In people 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%). 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 because of its extensive enterohepatic recirculation.
Several cases of naproxen toxicosis in dogs have been
reported. 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 of 35 mg/kg has been reported. Cats may be more
sensitive to naproxen toxicity than dogs because of their limited
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, a proton-pump inhibitor used to inhibit
gastric acid secretions, can be used instead of an H2
blocker at 0.5–1 mg/kg/day, PO, in dogs. Sucralfate (dogs: 0.5–1 g, PO,
bid-tid; cats: 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 (dogs: 1–3 mcg/kg,
PO, tid) has been shown to prevent GI ulceration when used concomitantly
with aspirin and other NSAIDs.
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 when 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 after exposure.
Acetaminophen is a synthetic nonopiate derivative of
p-aminophenol widely used in people for its antipyretic and analgesic
properties. Its use has largely replaced salicylates because of 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 two 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 seen unless the
dosage of acetaminophen exceeds 100 mg/kg. Clinical signs of methemoglobinemia
have been reported in 3 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
Methemoglobinemia and hepatotoxicity characterize
acetaminophen toxicosis. Renal injury is also possible. Acute
keratoconjunctivitis sicca has been reported in some dogs after 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 sulfhydryl 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 seven 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, because
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 in dogs only. Cimetidine should not be used in
cats. In vitro evidence indicates that use of cimetidine in cats can produce
more toxic metabolites of acetaminophen. S-Adenosyl methionine has been
suggested as an adjunct to manage acute or chronic hepatic injury at 18
mg/kg, PO, for 1–3 mo in dogs and cats.
Last full review/revision August 2014 by Safdar A. Khan, DVM, MS, PhD, DABVT