Lecture 22 - Urinary System Toxicology Flashcards
What makes the urinary system susceptible to toxicity?
High blood flow (_____% of cardiac output)
coupled with ____ size (___% of total bw)
High ________ demand: many of the renal
functions rely on ______ transport
Processes involved in concentrating urine
also concentrate ________
◦ The countercurrent mechanism progressively
_________ the concentration of toxicants
Metabolic activation of xenobiotics by
______ systems within the renal tubular
epithelium
High blood flow (25% of cardiac output)
coupled with small size (0.5% of total bw)
High metabolic demand: many of the renal
functions rely on active transport
Processes involved in concentrating urine
also concentrate toxicants
◦ The countercurrent mechanism progressively
increases the concentration of toxicants
Metabolic activation of xenobiotics by
enzyme systems within the renal tubular
epithelium
The urinary system receives __% of cardiac output
- ____% to renal cortex
- ___-___% to medulla
The urinary system receives 25% of cardiac output
- 90% to renal cortex
- 6-10% to medulla
Which part of the urinary system is most sensitive to toxicity?
the proximal tubules
How much oxygen is delivered to the urinary system?
10% of the body’s oxygen
How is renal function measured?
Renal function is clinically measured by serum renal
function markers BUN and creatinine
◦ Due to reserve capacity, 50-70% of the nephrons need to
be damaged for these markers to be significantly elevated
Describe mild renal toxicity
Renal function _______ using reserve capacity with _______ alterations found on urinalysis e.g. ______ and _______. Completely _______
Renal function continues using reserve capacity with minimal alterations found on urinalysis e.g. isosthenuria and proteinuria. Completely reversible
Describe acute renal failure
◦ Manifests as ______ GFR, ______ BUN, _______ creatinine, glucosuria, azotemia aminoaciduria, oliguria/anuria, renal enlargement and pain
◦ Polydipsia, nausea/vomiting, lethargy, anorexia, weakness
◦ Systemic sequelae: dehydration and metabolic acidosis
◦ Reversible with appropriate treatment
◦ Manifests as decreased GFR, increased BUN, increased creatinine, glucosuria, azotemia
aminoaciduria, oliguria/anuria, renal enlargement and pain
◦ Polydipsia, nausea/vomiting, lethargy, anorexia, weakness
◦ Systemic sequelae: dehydration and metabolic acidosis
◦ Reversible with appropriate treatment
Chronic renal failure results from?
Results from _____-term exposure to toxicants
__________ deterioration of renal function with
exhaustion of reserve capacity
Characterized by _____/_____,
isosthenuria, ____ BUN, ___ creatinine, uremia,
dehydration
Frequently ________
◦ Progresses to ___-__ renal disease (ESRD) with ________ loss of renal function
Results from long-term exposure to toxicants
Progressive deterioration of renal function with
exhaustion of reserve capacity
Characterized by polyuria/polydipsia,
isosthenuria, BUN, creatinine, uremia,
dehydration
Frequently irreversible
◦ Progresses to end-stage renal disease (ESRD) with permanent loss of renal function
Describe the characteristics of Ethylene Glycol (EG)
(Antifreeze Poisoning)
A colorless, odorless, sweet-tasting (?) liquid
List the sources of ethylene glycol
Antifreeze solutions (95% EG), windshield
de-icing agents, brake and transmission fluids,
polishes
Photographic solutions, paint solvent
Also in antifreeze & toxic: propylene glycol, methanol
10,000 dogs poisoned annually in US by ethylene glycol
Describe the toxicity and risk factors of ethylene glycol toxicity
Toxicity occurs throughout the year
◦ Most common in fall, winter and spring
Most cases involve dogs followed by cats
Other animals and birds are also affected
High mortality rate (78% in cats and dogs) –> Delays in presentation and diagnosis, tx limitations
Cats are more sensitive to ethylene glycol toxicity due to high baseline production of ?
oxalic acid
Why is Ethylene Glycol Toxicity So Common?
➢Abundance in households coupled with lack
of public awareness of its high potential for
toxicity
➢Palatability (somewhat pleasant taste) –> * Dogs avoid EG if other water sources are available?
* Dogs consume EG voluntarily even when water is available?
➢Relatively low lethal dose
Ethylene Glycol ADME
Rapid absorption from ____ tract and _____
◦ GI absorption is delayed when ____ is present
Distributes _____ throughout the body; peak
[plasma] in dog is reached in ? hrs
Metabolism occurs in the ____ and ___ to
yield toxic metabolites
EG and its metabolites are excreted within ___-__h mainly through the kidney; t½= 11h
Rapid absorption from GI tract and lungs
◦ GI absorption is delayed when food is present
Distributes quickly throughout the body; peak
[plasma] in dog is reached in1- 4h
Metabolism occurs in the liver and kidney to
yield toxic metabolites
EG and its metabolites are excreted within 24-
48h mainly through the kidney; t½= 11h
Ethylene gylcol metabolism
Important in understanding the toxicosis and making therapeutic choices
EG is oxidized by _____ to glycoaldehyde (1st rate limiting reaction)
Glycoaldehyde
Is _____ toxic than EG but it does not accumulate
Glycoaldehyde is readily metabolized by
___________ and ____________ to glycolic acid and via a minor pathway to glyoxal
Glycolic acid
Converted to _______ acid (2nd rate limiting
reaction) by ______- acid oxidase or ______-
dehydrogenase (LDH). Metabolism of glycolic
acid is slow → glycolic acid accumulation →
acidosis and nephrosis
Glyoxylic acid
More toxic than the other metabolites but…
◦ Has short t½ hence does not reach toxic levels
Important in understanding the toxicosis and making therapeutic choices
EG is oxidized by alcohol dehydrogenase
(ADH) to glycoaldehyde (1st rate limiting
reaction)
Glycoaldehyde
Is more toxic than EG but it does not
accumulate
Glycoaldehyde is readily metabolized by
mitochondrial aldehyde dehydrogenase and
cytosolic aldehyde oxidase to glycolic acid
and via a minor pathway to glyoxal
Glycolic acid
Converted to glyoxylic acid (2nd rate limiting
reaction) by glycolic acid oxidase or lactate
dehydrogenase (LDH). Metabolism of glycolic
acid is slow → glycolic acid accumulation →
acidosis and nephrosis
Glyoxylic acid
More toxic than the other metabolites but…
◦ Has short t½ hence does not reach toxic levels
Glyoxylic acid is metabolized to:
1. _____ acid via oxidation by _____ acid oxidase or ____
2. Formic acid
3. Glycine
* Reacts with _____ acid to form hippuric acid
Enters the amino acid pool via a pyridoxine-
dependent aminotransferase step
4. -hydroxy--ketoadipate by conjugation
with α-ketoglutarate
Glyoxylic acid is metabolized to:
1. Oxalic acid via oxidation by glycolic acid
oxidase or LDH
2. Formic acid
3. Glycine
* Reacts with benzoic acid to form hippuric acid
Enters the amino acid pool via a pyridoxine-
dependent aminotransferase step
4. -hydroxy--ketoadipate by conjugation
with α-ketoglutarate
Oxalic acid
◦ Excreted in ______
◦ Combines with calcium to form ________ ______, which is then deposited in renal ____, ____ vasculature and other ______
Oxalic acid
◦ Excreted in urine
◦ Combines with calcium to form calcium
oxalate
Calcium oxalate is then deposited in renal
tubules, brain vasculature and other tissues
The first and most important therapeutic target is the conversion of ethylene glycol to glycoaldehyde which is targeted by the two main drugs used for treatment of ethylene glycol toxicosis: ________ and _____.
These drugs work by competitively inhibiting ___.
Other potential sites that can be targeted include the conversion of glyoxylic acid to ____ and _____, which are promoted by administration of ______ and ________, respectively, thus reducing the formation of oxalic acid.
The first and most important therapeutic target is the conversion of ethylene
glycol to glycoaldehyde which is targeted by the two main drugs used for
treatment of ethylene glycol toxicosis, fomepizole and ethanol.
These drugs work by competitively inhibiting alcohol dehydrogenase.
Other potential sites that can be targeted include the conversion of glyoxylic
acid to glycine and -hydroxy-β-ketoadipate, which are promoted by
administration of pyridoxine and thiamine, respectively, thus reducing the
formation of oxalic acid.
What is the MOT of Ethylene Glycol?
EG and its metabolites are responsible
for the toxic actions:
◦ GI tract irritation: EG, calcium oxalate
◦ CNS depression: EG, glycoaldehyde, and
calcium oxalate
◦ Induction of metabolic acidosis and
electrolyte imbalance: acid metabolites
◦ Cytotoxicity: acid metabolites and reactive
oxygen species (due to inhibition of CYP450)
◦ Mechanical damage: Ca-oxalate crystals
What are the clinical signs of Ethylene glycol toxicity - Stage 1
Stage I: CNS Stage
___min – ___h
Attributable mainly to ___ and ______.
High levels of ______ acid also can cause CNS effects
◦ Mimics ______ _______ _______
◦ _____ tract irritation
◦ EG ______ serum osmolarity → PD/PU
◦ EG has an osmotic _______ effect (like ethanol)
and may _______ release of anti-diuretic hormone
Stage I: CNS Stage
30min – 12h
Attributable mainly to EG and aldehydes.
High levels of glycolic acid also can cause
CNS effects
◦ Mimics acute alcohol toxicosis
◦ GI tract irritation
◦ EG increases serum osmolarity → PD/PU
◦ EG has an osmotic diuretic effect (like ethanol)
and may inhibit release of anti-diuretic hormone
What are the clinical signs of Ethylene glycol toxicity in dogs - Stage 1
Animal is ________ and _______
Moderate _______, loss of ______ and ___ reflexes
Progressive ____ with ______-over and ___
Osmotic diuresis → marked ______ and _____
_____thermia
______ and ______ may result from gastric
irritation
Animal is inebriated and belligerent
Moderate depression, loss of withdrawal and
righting reflexes
Progressive ataxia with knuckling-over and
stumbling
Osmotic diuresis → marked polydipsia and
polyuria
Hypothermia
Nausea and vomiting may result from gastric
irritation
What are the clinical signs of Ethylene glycol toxicity - Stage 2
(___-___h)
______/______ stage
◦ Metabolic acidosis is attributable to ____ _____ especially ______ acid
◦ Ca++ sequestration as Ca-oxalate → ______ → impairment of ______ function
_______ subsides with metabolism of EG
but the metabolites cause severe acidosis
Clinical signs include vomiting, miosis,
tachycardia or bradycardia, tachypnea,
muscle fasciculation, depression,
hypothermia, and coma
Many animals ___ during this stage
(12-24h)
Cardiopulmonary/acidotic stage
◦ Metabolic acidosis is attributable to acid
metabolites especially glycolic acid
◦ Ca++ sequestration as Ca-oxalate →
hypocalcaemia → impairment of cardiac
function
Polydipsia subsides with metabolism of EG
but the metabolites cause severe acidosis
Clinical signs include vomiting, miosis,
tachycardia or bradycardia, tachypnea,
muscle fasciculation, depression,
hypothermia, and coma
Many animals die during this stage
List the DDx for Anion Gap
CAT MUDPILES
C- Carbon monoxide, cyanide
A- Aminoglycosides
T- Toluene/theophylline
M- Methanol/melamine-cyanuric acid
U- Uremia
D- Diabetic ketoacidosis
P- Propylene glycol
I - Infection/ischemia/iron
L - Lactate
E - Ethylene glycol/ethanol
S - Salicylates/starvation
How do you calculate plasma osmolarity?
What are the clinical signs of Ethylene glycol toxicity?? - Stage 3
Urine
Due to fluorescein dye added
to EG to trace leakages
How do you Tx Ethylene Glycol toxicity?
Initiate ASAP: <3h (cats), <5h (dogs)
Goal: stop EG going down its metabolic
pathway
