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
What are the clinical signs of Ethylene glycol toxicity - Stage 3
___-___h
_______ toxicity
Characterized by:
◦ Formation of ____-_____ crystals in the
kidneys
◦ Cytotoxicity of EG metabolites to renal
tubular epithelium
◦ Toxic effects of glycolic acid and glyoxylic acid
Elevate anion and osmolar gaps → renal edema
which compromises intrarenal blood flow →
renal failure
24-72h
Renal toxicity
Characterized by:
◦ Formation of Ca-oxalate crystals in the
kidneys
◦ Cytotoxicity of EG metabolites to renal
tubular epithelium
◦ Toxic effects of glycolic acid and glyoxylic acid
Elevate anion and osmolar gaps → renal edema
which compromises intrarenal blood flow →
renal failure
Anion Gap (AG)
The difference between measured serum
cations and anions. Calculated as:
Anion gap = [Na+] + [K+] – ([Cl-] + [HCO3-])
◦ It is also the difference between unmeasured anions
and unmeasured cations
Unmeasured anions: SO42-, PO42-, lactate,
ketones, *EG metabolites
Unmeasured cations: Ca2+, Mg2+ (sometimes K+)
AG is mainly due to a decrease in serum
HCO3- (used to buffer H+), and EG metabolites
that contribute to the unmeasured anions pool
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
Osmolality = # of particles/kg solvent
Osmolarity = # of particles/L solvent
The Osmolar gap is?
The difference between _____ and ______ serum osmolality
◦ Molecules that contribute the most to serum
osmolality are: ?
The difference between measured and calculated serum osmolality
◦ Molecules that contribute the most to serum
osmolality are: Na+, K+, Cl-, HCO3-, glucose
and urea
Osmolality is measured by _________ and normal values are ____-___ mOsm/kg
osmometry and
normal values are 280-310 mOsm/kg
Hyperosmolality occurs because
EG is an
osmotically active small molecule
How do you calculate plasma osmolarity?
Normal osmolar gap is
10 mOsm/L
EG intoxication increases osmolar gap to
> /= 60 mOsm/L
The osmolar gap increases because EG and its
metabolites are measured by an osmometer but
are not considered in the formula used to
calculate osmolarit
What are the clinical signs of Ethylene glycol toxicity?? - Stage 3
What are the clinical signs of Ethylene glycol toxicity in other cats?
Cats: signs are similar to those in dogs but there is
no polydipsia and depression is persistent
What are the clinical signs of Ethylene glycol toxicity in other cattle?
Staggering/ataxia, paraparesis, tachypnea, dyspnea,
recumbency, bradycardia initially with tachycardia
later, hemoglobinuria, epistaxis
What are the clinical signs of Ethylene glycol toxicity in other swine?
Depression, weakness, ataxia, knuckling of hind-
limbs, muscle tremors, loss of reflexes, ascites,
hydrothorax, weak heart sounds and recumbency
What are the clinical signs of Ethylene glycol toxicity in other chickens?
Listlessness, ataxia, ruffled feathers, dyspnea,
watery droppings, recumbent posture with
drooping wings, closed eyes with head
resting on the floor (propped by the beak),
and cyanosis of the comb
How do you Dx Ethylene glycol toxicity?
History of exposure
Clinical signs
Clinical pathology
Chemical analysis (GC, HPLC, colorimetric kits)
Examination of urine, oral cavity, vomitus, face
or paws with Wood’s lamp
Ultrasonography: renal cortical echogenicity
Postmortem picture
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
How do you treat ethylene glycol toxicity - Decontamination
◦ Emesis if within 30 min of exposure
Do not induced emesis in dogs/cats exhibiting
neurologic signs because of increased risk of aspiration
◦ Consider gastric lavage within 4 h if scout
radiograph reveals presence of ingesta
◦ Give repeated doses of activated charcoal except
for patients to be treated with ethanol orally
Activated charcoal inhibits ethanol absorption
◦ Consider use of saline cathartic
What are the antidotes for ethylene glycol toxicity?
- Ethanol: competitively inhibits ______ ______ b/c it has a higher affinity for ____ than EG
- 4-methylpyrazole (Antizol-Vet, _______): competitive alcohol dehydrogenase inhibitor
◦ Do not use the 2 antidotes together. Why?
Ethanol: competitively inhibits alcohol
dehydrogenase. Ethanol has a higher affinity
for enzyme than EG
4-methylpyrazole (Antizol-Vet,
fomepizole): competitive alcohol
dehydrogenase inhibitor
◦ Do not use the 2 antidotes together. Why?
Ethanol (alcohol) toxicosis would occur
How do you treat ethylene glycol toxicity supportively?
◦ Fluid therapy to correct dehydration and promote diuresis (helps in excretion of ethylene glycol and its metabolites)
◦ Give sodium bicarbonate to correct metabolic
acidosis
◦ Peritoneal dialysis may be needed to support renal function and aid in excretion of ethylene glycol and metabolites
◦ Control hypothermia if present, e.g., with blankets
◦ Fluid therapy to correct dehydration and promote diuresis (helps in excretion of ethylene glycol and its metabolites)
◦ Give sodium bicarbonate to correct metabolic
acidosis
◦ Peritoneal dialysis may be needed to support renal function and aid in excretion of ethylene glycol and metabolites
◦ Control hypothermia if present, e.g., with blankets
What are the risks of treating ethylene glycol toxicity?
- Emesis: useful early in the exposure but
presents a risk of aspiration because patients
are depressed - Fluid therapy is indicated for dehydration and
enhancement of excretion of EG and its
metabolites but can cause fluid overload if
patient is oliguric - Ethanol reduces EG metabolism to toxic
metabolites but increases osmolarity and
causes CNS depression
What is the prognosis of Ethylene glycol toxicity?
EG exposure has a very high potential for a
lethal outcome
Prognosis depends on dose ingested, rate of
absorption, and time interval between
exposure and treatment
Timely Dx and Tx are therefore vital
◦ Prognosis is good if Tx is initiated <3h after
exposure in cats and <5h in dogs
Propylene Glycol (PG)
Colorless, odorless viscous liquid
List the sources of Propylene Glycol (PG)
Semi-moist pet food:
3-13% PG
◦ Solvents, humectants, plasticizers, bacteriostats
in pharmaceuticals, cosmetics & food. Propylene
glycol is no longer used in cat foods
◦ Coolants, deicing solutions and automotive
antifreeze
◦ Used as a glucose precursor to treat ketosis
PG is _____ toxic than ethylene glycol
Less toxic than ethylene glycol
PG
Oral LD50 = 9 ml/kg (dogs)
What is the ADME of PG?
PG is rapidly absorbed from GI tract or after
inhalation
Metabolized in liver and kidney by alcohol
dehydrogenase and aldehyde dehydrogenase to
D- and L-lactic acid. L-lactic acid is rapidly
metabolized in the Krebs cycle, but D-lactic acid
is slowly metabolized → accumulates in plasma
→ lactic acidosis
Excreted in the kidney (12-55%) un-metabolized
or as a glucuronide conjugate
What is the MOT of PG?
Susceptible species: cats, dogs, cattle, horses
PG is an osmotic diuretic and a narcotic
Accumulation of lactic acid in brain causes
encephalopathy
PG induces Heinz body anemia in cats by
interacting with –SH groups in Hb
◦ Cats are particularly sensitive because their Hb
contains 8 sulfhydryl groups, and they have less ability
to conjugate propylene glycol with glucuronide
Greatest risk: Cats with high food intake
e.g. lactating queens and nursing kittens
What are the clinical signs of PG toxicity?
Signs are mainly attributable to acidosis and
narcosis
Cats/dogs: polyuria/polydipsia, dehydration,
decreased activity, depression, ataxia, muscle
twitching, drunkenness, hypotension
Cows: ataxia, depression and temporary
recumbency
Horses: pain, sweating, salivation, ataxia,
depression, recumbency, rapid shallow breathing
and cyanosis
Note: PG has been mistaken for mineral oil and given to horses as colic Tx!
How do you Dx PG toxicity?
History of exposure
Measurement of propylene glycol in serum
Clinical pathology: metabolic acidosis, elevated
anion gap associated with high blood lactic acid
How do you Tx PG toxicity?
Supportive
◦ IV fluids containing sodium bicarbonate
◦ Cats with Heinz body anemia recover with supportive
care
◦ A mare survived after gastric lavage and
administration of activated charcoal, Na-bicarbonate,
dexamethasone and vitamin C
