Renal and Hepatic Toxicity Flashcards
(46 cards)
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
2
Q
proximal convoluted tubules
A
Most common site of toxin induced injury
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
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
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
6
Q
action of parathyroid gland
A
mobilizes Ca
7
Q
action of calcitonin
A
puts calcium back into bone
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
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
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
11
Q
What does glycolic acid cause?
A
acidosis
12
Q
What does glyoxylic acid cause?
A
CNS signs
13
Q
What does oxalate/oxalic acid cause?
A
Renal damage and hypocalcemia by binding to calcium to form calcium oxalate
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
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
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
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
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
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
duration of therapy for animals with EG toxicity
* Therapy often required **up to 72 hours**
* Recovery can take **3-5 days if treated aggressively**
26
cholecalciferol/Vitamin D3 toxicity
* 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
MOA of cholecalciferol
* 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
clinical signs of cholecalciferol toxicity
* 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
diagnosis of cholecalciferol toxicity
* 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
differential diagnosis to cholecalciferol toxicity
* 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
treatment of cholecalciferol
* **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
grape and raisin toxicity
grapes, grape skin, and raisins can cause a**cute renal failure in some dogs**
33
MOA of grape toxicity
* **Unknown**
* **Lack of dose response** seen
* **No relationship between dose ingested** in dogs that died and those that survived
34
clinical signs of grape toxicity
* Initial signs is usually **vomiting followed by signs of acute renal failure:**
* hypercalcemia
* hyperphosphatemia
* increased Ca x PO4
* elevated BUN and serum creatinine
35
diagnosis of grape toxicity
based on **clinical signs of acute renal failure and known ingestion**
36
treatment of grape toxicity
* 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
how does dopamine help treat grape toxicity?
facilitates **kidney function and renal blood flow**
38
main goal of treating a grape toxicity?
keep the kidney working!
39
general liver toxicosis
* 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
acetaminophin toxicity
* 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
MOA of acetaminophen
* 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
clinical signs of acetaminophen toxicity
* 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
diagnosis of acetaminophen toxicity in cats
* **Cyanosis, methemoglobinemia, dyspnea**, weakness and depression, edema of paws and face
* **anemia** present in **75% of cats**
44
diagnosis of acetaminophen toxicity in dogs
* Signs associated with **acute centrilobar hepatic necrosis**
* nausea, vomiting, anorexia, abdominal pain, shock, tachypnea, tachycardia
45
other possible clinical signs of acetaminophen toxicity that could be diagnostic
* **Hemolysis**
* **Heinz body** in **cats and dogs** stained with NMB
* **elevated liver enzymes**
46
treatment of acetaminophen toxicity
* **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
