13 – NSAIDs and Acetaminophen

Question 1

Intro and important info to gather

Answer 1

• common misconception that if it is safe for humans = safe for pets
• any drug is toxic if dose is high enough
• dose-dependent vs. idiosyncratic drug reactions
• *active ingredient
• *strength/composition
• *estimated amount ingested
• *time ingested

Question 2

*NSAIDs: exposure scenarios

Answer 2

• Overdose of prescribed medication
• Combination therapy
• Accidental ingestion of improperly stored medications
• Well-meaning owner gives human OTC NSAID

Question 3

What are the most common NSAID toxicoses in companion animals?

Answer 3

• *OTC NSAIDs
• Ibuprofen and naproxen
  o Easily accessible and available, lack of understanding of risk

Question 4

NSAIDs: target organs

Answer 4

• *GIT, kidneys, CNS
• *exacerbated with dehydration
• Hepatotoxicity possible

Question 5

NSAIDs: mechanism

Answer 5

• Inhibition of COX expression=decreased prostaglandin production
  o Decrease GIT mucosal and renal blood flow
  o Decrease mucosal barrier repair and cell turnover
  o Decrease GI immune function
  o Decrease GI mucosal protection: bicarbonate, mucus secretion
• *relevant toxicokinetic: many are highly protein bound and undergo enterohepatic recirculation

Question 6

NSAIDs: companion animals (cats >dogs)

Answer 6

• *consider cats TWICE as sensitive as dogs
  o Deficient hepatic glucuronide conjugation
• Clinical presentations
  o Cats: renal failure
  o Dogs: GI ulcers
• **ferrets are very sensitive to ibuprofen

Question 7

NSAIDs: large animals

Answer 7

• Horses: narrow margin of safety
  o Ponies and foals considered more sensitive
• Uncommon in cattle and small ruminants

Question 8

NSAIDs: onset

Answer 8

• Within hours to days (dose-dependent)

Question 9

*NSAIDs: clinical features, GI

Answer 9

• Anorexia, abdominal pain
• Vomiting and diarrhea (“coffee grounds”)
• Dehydration, hypovolemia
• Underlying pathology (ulcers)
  o Risk of GI perforation and septic peritonitis
  o Pale MM
• Tachypnea, tachycardia
• Horses: colic, diarrhea, fever, anorexia

Question 10

*NSAIDs: clinical features, renal

Answer 10

• Painful abdomen, PU/PD
• Underlying pathology: acute renal insufficiency secondary to hypoperfusion
• Characteristic PM lesion in companion animals: *renal papillary necrosis
• *horses: right dorsal colitis

Question 11

*NSAIDs: clinical features, CNS

Answer 11

• Depression
• Ataxia
• Stupor or obtundation
• Seizures

Question 12

NSAIDs: death form (clinical features)

Answer 12

• GI perforation secondary to ulceration
• Acute kidney injury and renal failure
• CNS toxicosis

Question 13

NSAIDs: clinical pathology

Answer 13

• Dehydration
• +/- decreased total protein and anemia
• Leukocytosis with left shift
• Renal dysfunction
• Right dorsal colitis (horses): hypoalbuminemia

Question 14

NSAIDs: carprofen

Answer 14

• Idiosyncratic hepatopathy
• Acute hepatic necrosis
• Good prognosis with D/C drug and prompt medical treatment

Question 15

NSAIDs: aspirin (acetylsalicylic acid)

Answer 15

• 2 presentations
• Cats very sensitive: glucuronide conjugation
• Similar presentation to other NSAIDs
• High dose
  o Uncouples oxidative phosphorylation: pyrexia leading to hyperthermia, panting, seizures
  o Salicylates inhibits thromboxane production: bleeding is possible

Question 16

NSAIDs: management

Answer 16

• No specific antidote
• Decontamination if not contraindicated
• Aggressive symptomatic and supportive care
  o Gastroprotectants, renal support, CNS, frequent monitoring
• Other things to consider
  o IVLE for severely affected patients (CNS)
  o Therapeutic plasma exchange due to high protein binding
  o Horses: low stress, reduce work/exercise, low bulk diet

Question 17

NSAIDs: diagnosis

Answer 17

• History of exposure
• Quantification in blood or urine
• Imaging: loss of serosal detail if peritonitis

Question 18

NSAIDs: DDx

Answer 18

• Bleeding: anticoagulant rodenticides
• GI ulcers: corrosive products
• Acute kidney insufficency: grapes/raisins, lilies
• CNS depression: ethylene glycol, acetone, xylitol, ivermectin

Question 19

NSAIDs: prognosis

Answer 19

• Companion animals: excellent with prompt medical attention
• If perforation=grave prognosis

Question 20

Acetaminophen

Answer 20

• Common OTC pain reliever
  o COX-3 inhibitor: hypothalamus
• Previously recommended for dogs at LOW dose
• Common reason for presentation to the ER at the VMC

Question 21

Acetaminophen: exposure scenarios

Answer 21

• Accidental ingestion
• *lack of owner knowledge

Question 22

Acetaminophen: mechanism

Answer 22

• *bioactivation reaction
  o Production of reactive metabolite=depletion of cellular glutathione and oxidative injury
  o Damage to proteins and cell membranes

Question 23

Acetaminophen: target organs

Answer 23

• Blood: cats
• Liver: cats and dogs

Question 24

Acetaminophen: why are there species differences?

Answer 24

• Cats, ferrets&raquo_space; dogs
• *cats have deficient glucuronidation capacity and more readily saturated sulfation capacity

Question 25

Acetaminophen: dose-response

Answer 25

• *NO safe dose for cats
• Dogs: over 50mg/kg warrants decontamination and monitoring

Question 26

Acetaminophen: onset

Answer 26

• Within 4-12 hours of ingestion
• Within 24-36hrs: progression to hepatic necrosis, methemoglobinemia, oxidative damage hemolytic anemia
  o Yellow, brown MM
  o Jaundice, abdominal pain
  o CNS involvement: tremors, seizures, coma
  o *Can be fatal!

Question 27

Acetaminophen: clinical features

Answer 27

• Vomiting, anorexia, diarrhea
• Depression, lethargy
• Tachypnea, tachycardia
• Chemosis, facial edema, paw swelling

Question 28

Acetaminophen: clinical pathology

Answer 28

• Regenerative anemia
• *Blood smear: HEINZ BODIES
• Metabolic acidosis
• (met)hemoglobinuria

Question 29

Acetaminophen: PM

Answer 29

• Hepatomegaly with enhanced reticular pattern
• Jaundice

Question 30

Acetaminophen: histo

Answer 30

• Severe centrilobular hepatic necrosis
• Renal tubular nephrosis

Question 31

Acetaminophen: management

Answer 31

• Decontamination if NOT contraindicated
• *antidote: N-acetylcysteine
• Symptomatic and supportive care
  o Fluids, oxygen
  o Hemolytic anemia: blood transfusion
  o Hepatoprotectants
  o MetHb: methylene blue
• Other treatments to consider: cimetidine, vit C, bioflavonoids

Question 32

What is the mechanism of N-acetylcysteine?

Answer 32

• Increases hepatic glutathione synthesis
• Enhances sulfation
• Directly binds NAPQI (reactive metabolite)??

Question 33

Acetaminophen: diagnosis

Answer 33

• History of exposure, compatible C/S and clinical pathology findings
  o Some labs can analyze for it in blood and urine

Question 34

DDx for MetHb: acetaminophen

Answer 34

• Oxidizing agents
  o Heinz bodies: zinc, skunk musk, mothballs, phenolics, garlic/onion
  o Liver damage: sago palm, death cap mushroom, aflatoxin, microcystin

Question 35

Acetaminophen: prognosis

Answer 35

• Variable
• Any cat with any exposure: at least guarded
• Severe liver damage with no response to treatment=grave