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Toxicology > Renal and Hepatic Toxicity > Flashcards

Renal and Hepatic Toxicity Flashcards

1
Q

Why is the kidney a common site of toxicity?

A
  • Very high blood flow (22-25% cardiac output)
  • Concentration of compounds
  • Most important organ for the excretion of xenobiotics
    • mainly dependent on the water solubility of the toxicant
    • highly lipid soluble are reabsorbed across the tubular cells into the bloodstream again
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2
Q

proximal convoluted tubules

A

Most common site of toxin induced injury

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3
Q

Why are the proximal convoluted tubules the most common site of toxin induces injury?

A
  • Cytochrome P450 and cysteine conjugate B-lyase localize here
  • Bioactivation result in damage
  • Loose epithelium allow compounds to enter cells
  • Increased transport of anions, cations and heavy metals
    • accumulation and ischemic injury to epithelial cells
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4
Q

acute renal failure

A
  • Characterized by decreased GFR and renal azotemia
  • Caused by transient damage to tubule, glomerulus or vasculature.
  • Signs are vomiting, GI bleeding, PU/PD progressing to anuria, diarrhea, and tremors
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5
Q

chronic renal failure

A
  • Mostly related to pathological changes triggered by initial injury
  • Secondary changes are compensatory mechanisms
  • Signs are primarily edema, hypocalcemia and parathyroid activity, reduced RBC counts
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6
Q

action of parathyroid gland

A

mobilizes Ca

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7
Q

action of calcitonin

A

puts calcium back into bone

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8
Q

ethylene glycol

A
  • major ingredient in antifreeze
  • 2nd most common cause of fatal poisoning in animals
  • Most frequently used for malicious poisoning
  • Mostly exposed in Spring and Fall
  • Very high rate of lethality (80% +) due to delay in clinical signs
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9
Q

ethylene glycol toxicity

A
  • taste sweet to animals, so they like
  • Lethal dose in cats: 1.5ml/kg of undiluted antifreeze or about 1 tbsp of 50:50 antifreeze:water
  • Lethal dose in dogs is higher: 7ml/kg of undiluted antifreeze or 4.5 oz of 50% antifreeze
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10
Q

MOA of ethylene glycol

A
  • Major toxic agents are metabolites produced by action of alcohol dehydrogenase
    • glycolic acid
    • glyoxylic acid
    • oxalate/oxalic acid
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11
Q

What does glycolic acid cause?

A

acidosis

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12
Q

What does glyoxylic acid cause?

A

CNS signs

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13
Q

What does oxalate/oxalic acid cause?

A

Renal damage and hypocalcemia by binding to calcium to form calcium oxalate

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14
Q

Stage 1 clinical signs of ethylene glycol

A
  • 30 mins to 3 hours
  • “drunkenness”, ataxia, CNS depression
  • nausea, vomiting
  • PU/PD (dogs)
  • usually missed with unobserved ingestions
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15
Q

Stage 2 clinical signs of ethylene glycol

A
  • 12-24 hour
  • Tachypnea, tachycardia (or bradycardia)
  • often not severe and not recognized by owner
  • cats typically remain depressed
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16
Q

Stage 3 clinical signs of ethylene glycol

A
  • 12-72 hours
  • Most animals present at this stage
  • Polyuria progressing to oliguria and anuria
  • Lethargy, anorexia, vomiting, seizures
  • Oral ulcers, abdominal pain, dehydration, and enlarged kidneys
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17
Q

best method to diagnose ethylene glycol toxicity

A
  • Measuring EG concentration in blood
    • serum conc. peak in 1-6 hours
    • non-detectable in serum and urine by 24 hours
    • cats can be poisoned by levels below detection of many kits
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18
Q

other ways to diagnose ethylene glycol toxicity

A
  • Azotemia
  • Elevated BUN and creatinine in Stage 3
  • UA: low USG (1.008-1.012) crystalluria (w/in 6 hours)
  • Calcium oxalate crystals in kidney via ultrasound exam
  • Serum biochem profile: hyperglycemia, hypocalcemia
  • Anion and osmolal gap
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19
Q

how to measure anion gap

A
  • (Na+K) - (HCO3 + Cl)
  • anion gap >30 abnormal
  • osmolal gap >20 abnormal
20
Q

tx of ethylene glycol toxicity

A
  • Prevent formation of toxic metabolites
  • Achieved through admin of competitive inhibitors of alcohol dehydrogenase
    • 20% ethanol and NaHCO3 (traditional tx)
    • Fomepizole (4-MP) or Antizol
  • No benefit of giving ethanol or 4-MP if EG has already been metabolized
    • contraindicated in animals with renal failure
21
Q

why is sodium bicarbonate given with ethanol?

A

fix the metabolic acidosis

22
Q

why is decontamination with charcoal not a treatment for EG toxicity?

A

EG does not bind to charcoal

23
Q

prognosis of cats with EG poisoning

A
  • Peak plasma concentrations occur about 1 hour after ingestion
  • Survival highly dependent on treatment within 1st 3-4 hours
  • mortality rate at least 90%
24
Q

prognosis of dogs with EG poisoning

A
  • Peak plasma concentration occurs at 2-3 hours
  • Survival most likely if treatment is started within 6-8 hours of ingestion
  • Azotemia on admission offers slim survival chance
  • Renal failure indicates poor prognosis
25
Q

duration of therapy for animals with EG toxicity

A
  • Therapy often required up to 72 hours
  • Recovery can take 3-5 days if treated aggressively
26
Q

cholecalciferol/Vitamin D3 toxicity

A
  • Overdosage of vitamin supplements or exposure to rodenticide
  • Toxic at > 0.5 mg/kg, lethal around 10-15 mg/kg
  • Dogs and cats most affected
  • Less toxic than Warfarin
27
Q

MOA of cholecalciferol

A
  • Metabolized to 1,25-dihydroxycholecalciferol
  • Causes massive increase in serum calcium by:
    • increasing GI absorption
    • decreasing renal excretion
    • increasing synthesis of calcium binding protein
    • mobilizing bone calcium
28
Q

clinical signs of cholecalciferol toxicity

A
  • typically appear 36-48 hours
  • Anorexia, weakness, depression (non-descript signs)
  • Thirst and polyuria (PU/PD)
  • Calciuria
  • diarrhea, dark feces due to intestinal bleeding, vomiting
  • Hypertension, bradycardia, ventricular arrhythmia
  • Mineralization of tissues when Ca*P > 70 mg/L
29
Q

diagnosis of cholecalciferol toxicity

A
  • Diagnosis based on history of ingestion, clinical signs, and hypercalcemia
  • Most common finding is rapid increase in plasma P (>8 mg/dL) followed by increase in plasma Ca levels (>13 mg/dL)
  • Low PTH (stimulates release of Ca from bone)
  • Increased BUN and creatinine
  • Low USG with calciuria
  • High hydroxycholecalciferol level in bile and kidney
30
Q

differential diagnosis to cholecalciferol toxicity

A
  • Histological findings include mineralization in multiple organs (heart, pancreas, kidney, lung, stomach)
  • Ethylene Glycol
    • elevated kidney Ca 2000-3000pppm, EG >8000 ppm
    • Ca:P ratio in kidney 0.4:0.7, EG >2.5
  • Differentiate from paraneoplastic syndrome, juvenile hypercalcemia, and hyperparathyroidism
31
Q

treatment of cholecalciferol

A
  • Reduce dietary Ca and P
  • GI decontamination within 6-8 hours (usually too late)
  • Monitor serum Ca from admission and every 1-2 days
  • Normal saline and furosemide
    • promotes Ca excretion
  • Prednisolone (2-6 mg/kg)
    • reduce bone resorption, intestinal Ca absorption, and kidney Ca resorption
  • Calcitonin
    • side effects of anorexia, anaphylaxis, and emesis, inhibits bone resorption
  • Pamidronate can replace calcitonin but $$
  • Sucralfate or milk of magnesia for ulceration (also reduce P)
32
Q

grape and raisin toxicity

A

grapes, grape skin, and raisins can cause acute renal failure in some dogs

33
Q

MOA of grape toxicity

A
  • Unknown
  • Lack of dose response seen
  • No relationship between dose ingested in dogs that died and those that survived
34
Q

clinical signs of grape toxicity

A
  • Initial signs is usually vomiting followed by signs of acute renal failure:
    • hypercalcemia
    • hyperphosphatemia
    • increased Ca x PO4
    • elevated BUN and serum creatinine
35
Q

diagnosis of grape toxicity

A

based on clinical signs of acute renal failure and known ingestion

36
Q

treatment of grape toxicity

A
  • Recommend to treat following any ingestion of grapes at all
  • Emesis, lavage, activated charcoal for recent ingestion
    • one method not recommended over another
  • Fluid therapy for a min of 72 hours
  • Supportive therapy including:
    • furosemide
    • dopamine, mannitol, hemodialysis, or peritoneal dialysis
37
Q

how does dopamine help treat grape toxicity?

A

facilitates kidney function and renal blood flow

38
Q

main goal of treating a grape toxicity?

A

keep the kidney working!

39
Q

general liver toxicosis

A
  • The liver has a remarkable ability to regenerate itself because it is the first line of defense
  • Intrinsic injury may lead to steatosis, necrosis, cholestasis
    • occurs as dose-dependent reaction to a toxicant
    • often caused by a reactive product of xenobiotic metabolism
40
Q

acetaminophin toxicity

A
  • One of the most common causes of poisoning in both humans and animals
  • Metabolized in the liver by glucuronidation, sulphonation and oxidation pathways
    • oxidation pathway results in the highly reactive metabolite NAPQI (N-acetyl-p-benzoquinone imine)
  • Cats are extremely sensitive due to lack of glucouronidation (as low as 10 mg/kg)
41
Q

MOA of acetaminophen

A
  • Toxic effects due to formation of the metabolite NAPQI
    • when glutathione stores are depleted, NAPQI binds to macromolecules and proteins and causes:
      • liver tissue necrosis
      • increased methemoglobin
  • Erythrocyte injury is predominant problem in cats
    • methemoglobin and Heinz body production (present with anemia)
  • Hepatic effects dominate in dogs, mice, rats
42
Q

clinical signs of acetaminophen toxicity

A
  • characterized by methemoglobinemia and hepatotoxicity
    • usually accompanied by tachycardia, hyperpnea, weakness, and lethargy
  • Cats primarily develop methemogloninemia within a few hours, followed by Heinz body formation
  • Liver necrosis (dogs)
    • liver damage 24-36 hours after ingestion
    • centrilobar hepatocyte degeneration and necrosis
43
Q

diagnosis of acetaminophen toxicity in cats

A
  • Cyanosis, methemoglobinemia, dyspnea, weakness and depression, edema of paws and face
  • anemia present in 75% of cats
44
Q

diagnosis of acetaminophen toxicity in dogs

A
  • Signs associated with acute centrilobar hepatic necrosis
    • nausea, vomiting, anorexia, abdominal pain, shock, tachypnea, tachycardia
45
Q

other possible clinical signs of acetaminophen toxicity that could be diagnostic

A
  • Hemolysis
  • Heinz body in cats and dogs stained with NMB
  • elevated liver enzymes
46
Q

treatment of acetaminophen toxicity

A
  • Replace glutathione stores, increase productivity of the other 2 pathways, and manage the hematological signs
  • Early decontamination only if very recent
  • Give glutathione precursor N-acetylcysteine (NAC)
    • loading dose is 140 mg/kg via slow IV
    • follow w/ 70 mg/kg IV q 6 hrs for 24-48 hrs
    • use methionine if NAC not immediately available
  • Reduce methemoglobin levels with ascorbic acid
  • Can consider administering cimetidine in cats (efficacy much less than NAC)
  • Supportive care
    • fluids and blood transfusions given as needed
    • oxygen therapy for methemoglobinemia

Toxicology (8 decks)

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