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Toxicology 5172 (Fall 2014) > L5: Renal & Hepatic Toxicity (Martyniuk) > Flashcards

L5: Renal & Hepatic Toxicity (Martyniuk) Flashcards

1
Q

2nd leading cause of fatalities in small animals

A

ethylene glycol

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2
Q

3 types of active compounds in rodenticides**

A

anticoags
cholecalciferol/Vit. D3
neurotoxicants

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3
Q

Why is kidney a common site of toxicity?

A
  • very high blood flow (22-25% of cardiac output)
  • compounds concentrate
  • phase I/II enzymes present, allowing for bioactivation
  • most important organ for excretion of xenobiotics:
    • depends on water solubility of the toxicant
    • high lipid solubility xenobiotics are reabsorbed across the tubular cells into the bloodstream again
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4
Q

What happens at Bowman’s capsule?

A

where glomerular filtration occurs. 100% filtrate produced.

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5
Q

What happens at Proximal convoluted tubule?

A
  • Active and passive absorption
  • 80% filtrate reabsorbed
  • where most toxicosis occurs**
  • increased transport of anions, cations, heavy metals, accumulation and ischemic injury to epithelial cells
  • where Cytochrome P450 and cysteine conjugate b-lyase localize and bioactivate
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6
Q

What happens at loop of Henle?

A
  • H2O and salt conservation

- 6% filtrate reabsorbed

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7
Q

What happens at Distal Tubule?

A
  • where ADH acts
  • 9% filtrate reabsorbed
  • variable reabsorption, active secretion
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8
Q

What happens at Collecting tubule?

A
  • Variable salt and H2O reabsorption

- 4% filtrate reabsorbed

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9
Q

Chars. of ACUTE renal failure

A
  • char. by dec. GFR and subsequent renal azotemia
  • damage to tubule, glomerulus or vasculature (usually reversible)
  • symptoms: v, GI bleed, PU/PD –> anuria, lethargy, anorexia, depression, d, tremors
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10
Q

Chars. of CHRONIC renal failure

A
  • related to 2ary pathological changes triggered by initial injury
  • compensatory mechanisms that dec. glomerular fx & tubular and interstitial changes
  • Symptoms: edema, hypocalcemia, parathyroid activity, reduced RBCs, bloody urine, eventual death
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11
Q

Markers of kidney injury

A
  • changes in urine volume/osmolality/pH
  • glucosuria
  • BUN, creatinine (sensitive to hydration state)
  • Proteinuria
  • Presence of cellular enzymes in urine (alk phos, lactate dehydrogenase)
  • Inulin clearance
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12
Q

Ethylene Glycol overview

A
  • 2nd most common cause of fatal poisonings in animals
  • most frequently used for malicious poisoning**
  • very high rate of lethality (80+%) due to delays in presentation
  • antidote = ethanol IV
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13
Q

T/F: very rare that poultry and cattle experience ethylene glycol toxicity?

A

T

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14
Q

ethylene glycol MOA

A
  • acts like ethanol to produce early signs of “drunkenness”
  • glyoxal causes CNS signs
  • metabolized to glycolic acid, which causes acidosis
  • metabolism to oxalic acid combines with Ca to form insoluble crystals in renal tubules and causes injury
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15
Q

conversion of ethylene glycol to calcium oxalate crystals

A

alcohol dehydrogenase converts ethylene glycol to glycoaldehyde, which eventually –> oxalic acid –> calcium oxalate

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16
Q

how does ethanol work as antidote to ethylene glycol toxicity?

A

binds alcohol dehydrogenase, so ethylene glycol can’t be converted to glycoaldehyde and other toxic metabolites

17
Q

Stage 1 symptoms of ethylene glycol toxicity

A

30mins-3hrs

  • “drunkenness”, ataxia, CNS depression
  • nausea, vomiting
  • PU/PD
  • usually missed
18
Q

Stage 2 symptoms of ethylene glycol toxicity

A

12-24hrs

  • tachypnea, tachycardia (or brady)
  • not severe
  • cats depressed
19
Q

Stage 3 symptoms of ethylene glycol toxicity

A

12-72hrs

  • when most animals present**
  • PU –> oliguria, anuria
  • lethargy, anorexia, v, seizures
  • oral ulcers, abd. pain, dehydration, enlarged kidneys
20
Q

Dx of EG toxicity

A
  • measure EG conc. in blood
  • azotemia
  • elevated BUN/creat.
  • low urine SG
  • crystalluria
  • Ca oxalate crystals in kidney via ultrasound
  • Hyperglycemia, Hypocalcemia
  • inc. anion and osmolal gaps
21
Q

Tx of EG toxicity

A
  • emesis or lavage soon after ingesiton
  • NO act. charc. (doesn’t bind)
  • 20% ethanol and bicarb
  • Fomepizole and Antizol (ADH inhibitors that replace ethanol)
  • late stage tx: fluids, mannitol diuresis
22
Q

Cholecalciferol/Vit. D3 source

A

overdose of vitamin supplements or exposure to rodenticide

-affects dogs/cats most

23
Q

Cholecalciferol MOA

A

metabolized to 1,25-dihydroxycholecalciferol (which is also toxic)
-causes massive increases in serum calcium by inc. GI absorption, dec. renal excretion, inc. synthesis of Ca binding protein, and mobilizing bone C

24
Q

Symptoms of cholecalciferol toxicity

A
  • 36-48hrs later
  • anorexia, weakness, depression
  • PU/PD, low urine SG due to effects of Ca on vasopressin activity
  • Caciuria
  • d/v, hypertension, bradycardia, ventricular arrythmia
  • mineralization of tissues
25
Q

Dx of cholecalciferol toxicity

A
  • based on Hx, CS, hypercalcemia
  • rapid inc. in plasma phosphorus followed by inc. in plasma Ca lvls
  • low PTH
  • inc. BUN/creatinine
  • low spec grav with calciuria
  • high hydroxycholecalciferol lvls in bile/kidney
26
Q

Differential dx of cholecalciferol toxicity

A
  • mineralization in multiple organs (heart, pancreas, kid, lung, stomach)**
  • ethylene glycol
  • differentiate from paraneoplastic syndrome, juvenile hypercalcemia, and hyperparathyroidism
27
Q

Tx of cholecalciferol toxicity

A
  • reduced dietary Ca and phosphorus
  • GI decon if early
  • normal saline and furosemide**
  • pred (reduces Ca reabsorption)
  • Calcitonin (pushes Ca back into bones)
  • Aredia (a calcitonin replacer)
  • sucralfate for ulceration and to reduce P
28
Q

Grape/raisin toxicity overview (everything - tx)

A
  • can cause renal failure in some dogs
  • symptoms: v, crystal formation?, signs of acute renal failure
  • unknown MOA
  • clin path: hypercalcemia, hyperphosphatemia, elevated BUN/creat
  • poor prognosis
29
Q

Tx of grape toxicity

A
  • emesis, lavage, act. charc. if recent
  • fluids
  • supportive tx: furosemide, DA (increases filtration rates in the kidney), mannitol, hemodialysis, peritoneal dialysis
30
Q

3 main roles of liver

A

detoxification
metabolism
reproduction (produces vitellogenin to make eggs)

31
Q

intrinsic injury of liver –>

A

steatosis (retention of lipids), necrosis, cholestasis

  • occurs as dose-dependent rxn to a toxicant
  • often caused by reactive products of xenobiotic metabolism
32
Q

Acetaminophen overview

A
  • metabolized by liver

- cats extremely sensitive due to lack of glucuronidation

33
Q

Acetaminophen MOA

A
  • interferes with endoperoxidase
  • toxic effects due to form. of metabolite NAPQI
  • erythrocyte injury is predominant problem in cats (MetHb/Heinz bodies formed)
  • hepatic effects dominate in dogs, mice, rats (centrilobular hepatocyte degeneration/necrosis)
34
Q

Symptoms of acetaminophen

A
  • MetHb and hepatotoxicity accompanied by tachycardia, hyperpnea, weakness, lethargy
  • cats primarily develop metHb and Heinz bodies
  • centrilobular necrosis in dogs
35
Q

Dx of acetaminophen

A

Methb
Hemolysis
Heinz bodies
anemia in 75% of cats
-elevated alanine transferase and aspartate aminotransferase
-elevation of prothrombin time if liver damage severe
-progressive decrease in serum cholesterol and serum albumin

36
Q

Tx of acetaminophen

A
  • early decon
  • N-acetylcysteine (NAC)
  • cimetidine (Histamine receptor antagonist)
  • Ascorbic acid to reduce MetHb
  • supportive care (fluids, blood transfusion, O2)
37
Q

cimetidine MOA

A

histamine receptor antagonist; makes stomach less acidic to protect it from ulcers/other adverse effects

38
Q

NAC MOA

A

converts NAPQI to non-toxic compound using glutathione (phase II metabolic rxn)

Toxicology 5172 (Fall 2014) (8 decks)

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