Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

General

• As a class, the NSAIDs are prevalent in most households in the United States; thus they pose considerable exposure potential
• Animals may become poisoned by accidental ingestion (more common in dogs) or inappropriate administration by owners.
• Long-term use of NSAIDs in the management of orthopedic disease predisposes some animals to toxicosis.

Source

• Aspirin and the salicylates are carboxylic acid NSAIDs present in numerous over-the-counter sources that range from aspirin and arthritis cremes (methyl salicylate) to bismuth subsalicylate (e.g., Pepto-Bismol).
• Propionic acids are a class that includes ibuprofen (e.g., Advil, Nuprin), ketoprofen (Orudis), carprofen (Rimadyl), and naproxen.
• Enolic acids include oxyphenbutazone, phenylbutazone, piroxicam.
• Acetic acids include etodolac (EtoGesic), sulindac, indomethacin.

Species

• Dogs, cats, horses (foals) primarily
• Older and younger animals at greater risk of toxicosis

Clinical Signs :

GASTROINTESTINAL

• Vomiting
• Anorexia
• Colic
• Hematemesis
• Melena
• Jaundice
• Hepatic encephalopathy

CENTRAL NERVOUS SYSTEM

• Depression
• Possibly seizures

OTHER SIGNS

• Hyperthermia
• Coagulopathy
• Methemoglobinemia in cats

RENAL

• Dehydration
• Oliguria

CLINICAL PATHOLOGY

• Metabolic acidosis: elevated anion gap suggests salicylate intoxication
• Decreased serum albumin concentration
• noted with phenylbutazone intoxication due to protein-losing enteropathy
• NSAID-induced gastric or intestinal ulcers and those that cause nephrotoxicity
• Hyperkalemia, increased blood urea nitrogen and creatinine concentrations with nephrotoxicity • Elevated serum alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase concentrations and hyperbilirubinemia associated with hepatotoxic syndrome.

 LESIONS

• Erosions of the gastrointestinal mucosa
• Renal papillary necrosis, especially in horses

 Toxicity

• Cats more susceptible because of relatively low capacity of hepatic glucuronyl transferase system
• Dehydration
• therapeutic dose of phenylbutazone may be a toxic dose
• predisposes animals to nephropathy
• A great deal of individual variability in doses that may elicit toxicosis
• A dog can have gastritis after ingesting one 325-mg tablet of aspirin.
• Repeated dosing increases the likelihood of toxicosis
• Most over-the-counter products used by humans are developed for a 70-kg man, not a 4-kg dog.
• Aspirin
• cat: >25 mg/kg
• dog: 15 mg/kg every 8 hours
• Ibuprofen
• dog: 50–100 mg/kg
• Indomethacin
• dog: gastric ulcers may develop at doses of 2 mg/kg or greater
• Naproxen
• dog: 220-mg dose may cause acute gastric ulceration
• Phenylbutazone
• horses: 8.8 mg/kg per day for 4 days may induce toxicosis

 Mechanism of Action:

 INHIBITION OF THE CYCLOOXYGENASE ENZYME SYSTEM

• Mediates production of cyclic endoperoxides from arachidonic acid to yield prostaglandins
• Two isoforms of the cyclooxygenase (COX) enzyme encoded by different genes
• COX-1
• COX-2
• Most antiinflammatory, analgesic, and antipyretic actions are caused by inhibition of COX-2.
• Most adverse effects are caused by inhibition of COX-1.
• COX-1 is the constitutive isoform, is present in almost all tissues, is produced continuously, and is involved in tissue homeostasis.
• COX-2 is the inducible isoform, is found in macrophages, fibroblasts, chondrocytes, epithelial, and endothelial cells, is highly regulated, and is produced in large amounts in response to infection or the presence of cytokines.

 GASTROINTESTINAL TOXICOSIS

• Inhibition of COX isozymes
• inhibition of prostaglandin E and prostaglandin I
• decreased cytoprotective properties of gastric mucus
• increased hydrogen ion release from the gastric gland through H+,K+–adenosine triphosphatase system
• Direct drug effects
• acidic nature of some NSAIDs decreases mucosal barrier
• uncoupling of oxidative phosphorylation decreases mucous barrier function
• potential of ion trapping of acidic NSAIDs results in a higher local concentration.

NEPHROTOXICITY

• Inhibition of prostaglandin synthesis and renal blood flow
• Blocks production of prostaglandin I, prostaglandin E, and prostaglandin D
• increased vascular resistance
• constriction of renal capillary beds
• redistribution of blood away from the medulla •

 Vasoconstriction and medullary ischemia that cause renal papillary necrosis

HYPERTHERMIA

• More commonly associated with aspirin
• Uncoupling of oxidative phosphorylation

HEPATOTOXICITY

• More commonly associated with carprofen (Rimadyl)
• Mechanism not well understood
• Thought to be an idiosyncratic susceptibility

 Diagnosis

• History of exposure
• Clinical signs
• Clinical pathology
• blood in stool
• increased anion gap (aspirin)
• Serum drug concentration
• available for salicylates and ibuprofen in many hospitals
• not a useful tool in the treatment of a poisoned veterinary patient Treatment
• No specific antidote

DECONTAMINATION

• Emesis for recent ingestion for species capable of vomiting
• Activated charcoal, kaolin, and sorbitol cathartic (Toxiban) to adsorb any drug remaining in the gastrointestinal tract
• Gastric lavage or whole-bowel irrigation for large overdoses if necessary
• formation of bezoars (concretions) in the gastrointestinal tract .

INCREASED ELIMINATION

• Aspirin: urinary alkalinization with sodium bicarbonate
• Repeated dosing of activated charcoal
• Many NSAIDs have enterohepatic recycling.

 SUPPORTIVE AND SYMPTOMATIC THERAPY

• Fluid treatment of dehydrated patients
• Transfusion therapy if animal is anemic
• Gastrointestinal mucosal protection
• may prevent further damage to the gastric mucosa
• sucralfate
• cimetidine
• omeprazole
• misoprostol

        prostaglandin replacement literature shows mixed results

• Acid-base status
• Use of bicarbonate should be closely monitored for possible development of pulmonary edema
• Hyperthermia
• primarily due to salicylate intoxication
• cooling blankets needed
• Control of seizures
• diazepam

 Prognosis

• Most gastrointestinal lesions are reversible.
• Perforation of the intestine has a more guarded prognosis because of the possible presence of peritonitis.
• Most renal effects are reversible after discontinuation of the drug.
• Renal papillary necrosis is a permanent change that may not adversely affect renal function in horses.