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Veterinary Toxicology > NSAIDs Toxicology > Flashcards

NSAIDs Toxicology Flashcards

1
Q

What species are most susceptible to NSAIDs toxicosis?

A

70% of cases involve dogs

25% of cases involve cats

+ horses, especially foals

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2
Q

What are the most common sources of NSAIDs? What are the 3 main toxic principles?

A

anti-inflammatories, analgesics, antipyretics

  1. carboxylic acids - salicylic acids (aspirin), propionic acids (ibuprofen), acetic acids
  2. enolic acids - pyrazolones, oxicams
  3. COX-2 selective inhibitors - -ibs
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3
Q

Where are NSAIDs well absorbed? Metabolized? Excreted?

A

NSAIDs are weak acids and are well absorbed from the stomach and proximal intestine, highly bound to plasma proteins (albumin) with a low volume of distribution and slow clearance

liver - phase I and II reactions

kidneys (faster in alkaline urine) and bile

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4
Q

What 5 NSAIDs undergo enterohepatic recirculation?

A
  1. Indomethacin
  2. Ibuprofen
  3. Naproxen
  4. Flunixin
  5. Piroxicam
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5
Q

What 3 pathways do NSAIDs undergo during hepatic metabolism?

A
  1. CYP450 oxidation
  2. UGT glucuronidation (conjugation)
  3. sulfotransderase conjugation
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6
Q

Why do cats have an increased toxicity to NSAIDs?

A

deficient in glucuronidation

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7
Q

What are 5 risk factors for developing NSAID toxicosis?

A
  1. NSAIDs prevalent in households = high likelihood of accidental ingestion by pets
  2. inappropriate administration to pets by owner
  3. long-term use (orthopedic disease)
  4. older and younger animals at greater risk
  5. drug interactions with corticosteroids, diuretics, anticoagulants, phenobarbital, etc.)
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8
Q

What 4 aspects do other drugs commonly interact with the pharmacokinetics of NSAIDs?

A
  1. absorption
  2. compete for protein-binding
  3. increase or decrease metabolism rate
  4. increase or decrease excretion rate
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9
Q

What 5 pathological states increase risk factors for developing NSAID toxicosis?

A
  1. dehydration
  2. cardiac disease
  3. diminished hepatic or renal function
  4. GI disease
  5. hypotension and hypovolemia, commonly from anesthesia, severe trauma, and surgery
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10
Q

What affects the toxicity of NSAIDs?

A
  • dose
  • length of exposure
  • drug
  • animal species (cats!)
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11
Q

What is the mechanism of toxicity of NSAIDs? What other drug has similar actions?

A

inhibits the biosynthesis of prostanoids (PGE2, PGF2α, PGD2, PGI2, TXA2) by blocking cyclooxygenase

glucocorticoids inhibit phospholipase A2 and C, which produces arachidonic acid, which COX metabolizes into prostanoids

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12
Q

What are the 2 isoforms of cyclooxygenase that NSAIDs affact?

A

COX1 - constitutive and found in almost all tissues involved in tissue homeostasis

COX2 - inducible and highly regulates

BOTH have physiological and pathological roles

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13
Q

What NSAID irreversibly binds cyclooxygenase?

A

salicylates

  • reversible for others
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14
Q

What are the major actions of PGE2 on vasculature, kidneys, and GI?

A

vasodilation, increases permeability

diuresis, natriuresis, renin release

reduces gastric acid and pepsin secretion, stimulates gastric mucous and fluid secretion, and duodenal bicarbonate secretion

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15
Q

What are 5 major actions of PGI2 (prostacyclin)?

A
  1. vasodilation
  2. inhibits platelet aggregation
  3. renin release
  4. reduced gastric acid secretion
  5. stimulates gastric mucus and fluid secretion and duodenal bicarbonate secretion
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16
Q

What are the 2 major actions of PGD2?

A
  1. vasodilation
  2. inhibits platelet aggregation
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17
Q

What are the 2 major functions of PGF2α?

A
  1. bronchoconstriction
  2. uterine contraction
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18
Q

What are the 2 major functions of TXA2 (thromboxane A2)?

A
  1. platelet aggregation and activation
  2. vasoconstriction
19
Q

What 7 body systems are affected by NSAID toxicity?

A
  1. GI**
  2. renal*
  3. blood
  4. hepatic
  5. cardiovascular
  6. CNS
  7. immune system
20
Q

What are the main 3 mechanisms of NSAID-induced GI injury?

A
  1. COX-1 inhibition —> reduced mucosal blood flow and mucus/bicarbonate secretion, impaired platelet aggregation
  2. COX-2 inhibition —> reduced angiogenesis and increased leukocyte adherence
  3. epithelial damage
21
Q

How does COX inhibition reduce mucosal defense?

A

COX inhibition causes a decrease in PGE2 and PGI2 production, increasing the susceptibility to injury by luminal toxicants through….

  • decreased gastric blood flow, mucus and bicarbonate secretion, and platelet aggregation
  • increased gastrin and HCl secretion
22
Q

How does COX inhibition affect the normal repair processes?

A

impairs restitution (migration of healthy cells from gastric pits to injury) and ulcer healing by…

  • reducing blood flow
  • inhibiting cell proliferation
  • increasing apoptosis
  • inhibiting angiogenesis
23
Q

In what 2 ways does COX inhibition cause blood vessel damage?

A
  1. stimulates neutrophil adherence to vascular endothelium, causing obstruction of normal blood flow and ischemia
  2. adherent neutrophils release proteases and free radicals, injuring the endothelium and causing cell death
24
Q

What are the 3 major effects of TXA2 inhibition?

A
  1. inhibition of platelet activation and aggregation
  2. loss of vasoconstrictor effect
  3. prolonged bleeding time
25
Q

What is the classic hypothesis of COX-1 and COX-2 roles in the GI tract? What needs to be considered?

A

adverse effects of NSAIDs are due to the inhibition of constitutive COX-1 whereas anti-inflammatory, anti-pyretic, and analgesic actions are due to the inhibition of inducible COX-2

too simplistic: downplays the role of COX-2 in the GI tract mucosa, where there is evidence that COX-2 is constitutive in GI tract and selective COX-1 inhibition does not cause gastric damage (both need to be inhibited)

26
Q

How do COX-1 and COX-2 compare? What NSAIDs inhibit them? What is the outcome of that inhibition?

A

COX-1 = housekeeping, regulates mucosal blood flow, mucus, and HCO3-, adaptive cytoprotection - blocked by conventional NSAIDs, causing ulceration and attenuation of adaptive cytoprotection

COX-2 = adaptive cytoprotection, healing by cell proliferation, angiogenesis, and maturation of granulation tissue - blocked by selective NSAIDs, causing a delay in ulcer healing and attenuation of adaptive cytoprotection

both contribute to GI injury

27
Q

What are the beneficial effects of COX-2 on the heart, blood vessels, kidney, stomach, and intestine?

A

myocardial protection

PGI2 production, endothelial protection

salt/water homeostasis, renin synthesis, blood flow regulation

ulcer healing

mucosal homeostasis

28
Q

In what 2 ways do NSAIDs induce epithelial damage? What induced greater adverse effects?

A
  1. uncouple oxidative phosphorylation, which decreases ATP and the ability to regulate cell functions
  2. reduces barrier characteristics of the mucus gel layer by decreasing hydrophobicity of the mucus

ion trapping and enterohepatic recirculation increase local NSAID concentration

(parenteral or rectal administration does NOT prevent GI injury)

29
Q

What is the major sign of Indomethacin toxicosis in dogs?

A

gastric and intestinal mucosal ulceration/hemorrhage

30
Q

NSAIDs GI injury summary:

A
31
Q

What are the 4 roles of PGE2 and PGI2 in the kidney? When is the role of prostaglandins most important?

A
  1. regulate vascular tone and blood flow
  2. counteract vasoconstrictive effects of angiotensin II and NE
  3. renin release
  4. regulation of water and salt balance

dehydration, volume constriction, and hypotension

32
Q

What are the 3 renal effects of COX inhibition?

A
  1. decreased renal PGE2 and PGI2 cause an increase in renal vasculature resistance and vasoconstriction leading to medullary ischemia and papillary necrosis
  2. impairs tubular function and inhibits renin release
  3. acute allergic interstitial nephritis
33
Q

How does canine Indomethacin toxicosis present in the kidneys?

A

papillary necrosis

34
Q

What is the most common cause of hepatotoxicity with NSAID toxicosis?

A

repeated use of Carprofen (Rimadyl) —> 33% of cases seen in Labrador Retrievers

35
Q

What are the 2 possible mechanisms of hepatotoxicity from NSAID toxicosis?

A
  1. metabolic idiosyncrasy or immunologic response to reactive metabolites when glucuronide metabolites haptenize hepatocyte proteins and cause hypersensitivity
  2. induces mitochondrial permeability transition (MPT)
36
Q

How does COX function in the liver? What happens upon inhibition?

A

forms TXA2, a potent vasoconstrictor and stimulus for platelet aggregation

decreased TXA2 = decreased platelet aggregation and vasoconstriction = increased bleeding times

37
Q

In what dogs should NSAIDs be used with extreme caution?

A

dogs with thrombocytopenia or bleeding disorders, like von Willebrand’s disease (Dobermans, Shelties, GSDs, terriers)

38
Q

What additional mechanisms of toxicity does Aspirin (Salicylate) have?

A
  • uncouples oxidative phosphorylation (OXPHOS) by carrying protons across the inner mitochondrial membrane into the matrix, diminishing the proton gradient and causing ATP to be dissipated (elevated temp)
  • reduced ATP promotes anaerobic metabolism leading to elevations of lactate, ketones, and pyruvate —> metabolic acidosis
  • thus, stimulates respiratory center in the medulla, causing hyperventilation and respiratory alkalosis
39
Q

What clinical signs are associated with Salicylate toxicosis?

A
  • hyperthermia and metabolic acidosis due to OXPHOS uncoupling
  • hyperventilation, respiratory alkalosis
  • vomiting, diarrhea, dehydration
  • gastric ulceration and hemorrhage
  • tinnitus
  • restlessness, tremors, seizures, depression, coma
40
Q

What GI signs are associated with NSAID toxicosis?

A
  • upset —> ulcers —> renal effects
  • anorexia, nausea, vomiting (hematemesis)
  • ulcers
  • abdominal pain
  • diarrhea, melena
  • GI perforation with abdominal distension
41
Q

What renal, hepatic, CNS, hematological, an CVS signs are associated with NSAID toxicosis?

A
  • acute rheumatic fever, PU/PD, decreased GFR, oliguria, uremia
  • anorexia, ascites, icterus, hepatic encephalopathy, weight loss
  • depression, drowsiness, stupor, hyperalgesia, ataxia, seizures, behavioral changes
  • anemia, coagulation defects, methemoglobinemia
  • heart attack and strokes in humans
42
Q

How is NSAID toxicosis diagnosed?

A
  • history, clinical signs, pathology
  • abdominal radiographs
  • GI imaging by ultrasound
  • endoscopy for gastric ulcers
  • serum NSAID concentration
43
Q

When is emesis and activated charcoal contraindicated for NSAID toxicosis? What treatment is done?

A

prior vomiting/CNS signs
GI bleeding

  • discontinue NSAID use
  • supportive IV fluids and blood transfusion for extremely anemic patients
  • surgical intervention in those with perforated GI tract
  • Diazepam and Barbiturates for seizures
44
Q

What 4 GI protectants can be used for treatment of NSAID toxicosis?

A
  1. histamine (H2) receptors - Cimetidine, Ranitidine, Famotidine
  2. PPI - Omeprazole and Pantoprazole suppress acid secretion
  3. PGE1 analogs - Misoprostol
  4. Sucralfate - protects ulcers from acids and enzymes

Veterinary Toxicology (29 decks)

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