Lecture 23 Flashcards
Name the plants the contain soluble oxalates.
More than 30 plant species all over the USA.
Beets and docks (Rumex sp.), Halogeton sp., lamb’s
quarter (Chenopodium sp.), greasewood (Sarcobatus
sp.), rhubarb (Rheum sp.), soursob (Oxalis cernua),
Setaria, Kochia, Amaranthus, etc
Soluble Oxalates ADME:
Soluble oxalates are _________ absorbed from the ____
tract and ______ excreted.
Soluble oxalates are rapidly absorbed from the GI
tract and readily excreted
Which species are susceptible to Oxalate toxicity?
livestock (most commonly sheep and cattle) and companion animals
Label the plants pictured below.
What toxin do these plants possess?
What is the MOT of oxalates?
What are the clinical signs of oxalate toxicity?
- Attributable to hypocalcaemia
◦ Muscle tremors, tetany, seizures, weakness,
incoordination, reluctance to move, recumbency,
depression and coma
◦ Rumen atony, bloat, teeth grinding, slobbering
◦ Bradycardia - Vomiting, ^ BUN and weight loss occur in
animals that do not die acutely
How do you Dx oxalate toxicity?
History and compatible clinical signs
Plant identification and occurrence of Ca-
oxalate crystals in kidneys
Oxalate concentration measured in forage
How do you Tx oxalate toxicity?
Small animals: induce ________, give _______ products (_____ or ______ to bind oxalates)
Administer ______ ________: _______ _____ (1:3) to bind oxalates in gut
Give IV ________ to animals with renal insufficiency
Small animals: induce emesis, give dairy
products (milk or yogurt to bind oxalates)
Administer dicalcium phosphate: sodium
chloride (1:3) to bind oxalates in gut
Give IV fluids to animals with renal insufficiency
Lilium and Hemerocallis are also called?
day lily, tiger lily, Easter lily
Which species are susceptible to lilium and hemerocallis toxicity?
very toxic to cats (the only known susceptible species)
What toxin(s) do lilium and hemerocallis plants possess?
unknown water-soluble toxin. Leaves and flowers
are toxic.
What is the toxic dose for lilium and hemerocallis plants?
2-3 leaves are fatal to cats
Lily Toxin ADME:
The lily toxin is thought to be ________ absorbed based on ____ ______-ingestion (5- 10 min) appearance of clinical signs
◦ _______ emesis lessens the clinical signs
___________ is unknown
Elimination is thought to occur within ___ hrs but clinical signs last for several days due to _____ damage
The lily toxin is thought to be rapidly absorbed based on early post-ingestion (5- 10 min) appearance of clinical signs
◦ Early emesis lessens the clinical signs
Metabolism is unknown
Elimination is thought to occur within 48h but clinical signs last for several days due to renal damage
What is the MOT of Lily toxicity?
Renal ______ epithelial cell damage. Exact mechanism is ______.
Two components are necessary for acute renal failure to occur:
(i). ______ action of the toxin(s) on the renal _____ epithelium resulting in cellular damage
(ii). Severe dehydration due to _____
Renal tubular epithelial cell damage. Exact mechanism is unknown.
Two components are necessary for acute renal failure to occur:
(i). Direct action of the toxin(s) on the renal tubular epithelium resulting in cellular damage
(ii). Severe dehydration due to polyuria
What are the clinical signs of Lily toxicity?
Most cases occur __-__ weeks after Easter
Initially: depression, ______, vomiting, salivation and _______ weakness
Later: _______ followed by dehydration, ____ and recumbency.
Death occurs in __-___ days
Most cases occur 1-3 weeks after Easter
Initially: depression, anorexia, vomiting, salivation and progressive weakness
Later: polyuria followed by dehydration, anuria and recumbency.
Death occurs in 3-7 days
How do you Dx lily toxicity?
Recognition of exposure
Clinical signs, clinicopathology and PM lesions
Serum chemistry and urinalysis
How do you Tx lily toxicity?
- Decontaminate: _______, give ______ ______ and a _______
◦ If vomiting has already occurred, give an ____-_____, _____ _______ and a _______ - Anuric patients
◦ Correct ________ and impose fluid diuresis (give __-__ times amount of maintenance fluid)
◦ Perform peritoneal _______ or ___________
- Decontaminate: emesis, give activated charcoal and a cathartic
◦ If vomiting has already occurred, give an anti-emetic, activated charcoal and a cathartic - Anuric patients
◦ Correct dehydration and impose fluid diuresis (give 2-3 times amount of maintenance fluid)
◦ Perform peritoneal dialysis or hemodialysis
Grapes and raisins come from the genus ______ and raisins (dried grapes with ~ ___% moisture content)
Vitis, 15
Which species are susceptible to grape toxicity?
Poisoning in dogs has been reported since mid 1990s. No unambiguous case of grapes/raisins toxicosis in cats but anecdotal evidence suggests cats and ferrets may be susceptible
Which grapes are toxic?
All types and colors of grapes/raisins are toxic
Raisin colors vary as a result of the different drying processes; a dark purple or black raisin is sun-dried, a light brown raisin is mechanically dehydrated, and
yellow raisins are mechanically dried and treated with sulfur dioxide.
What is the toxic dose of grape toxicity?
Toxic dosage: varies widely
◦ Raisins: 2.8-36.9 g/kg; grapes: 19.8 to 150.3 g/kg
◦ 4–5 grapes were implicated in death of an 8.2-kg dog
◦ But…some dogs will consume grapes with impunity and not get poisoned
Although toxicity increases with increasing amounts ingested, some animals
were asymptomatic after ingesting as much as 1 kg of raisins
What toxins do grapes possess?
The toxins in grapes/raisins are yet to be confirm
It has recently been proposed that tartaric acid
and potassium bitartrate are the toxic principles
in grapes/raisins. This is based on:
1) Toxicity of potassium bitartrate (found in cream
of tartar and home-made playdough) is
characterized by similar clinical signs and proximal
renal tubule damage as grapes/raisins
2) Exposures to tamarinds, which are uniquely high
in tartaric acid, cause severe vomiting and acute
renal failure in dogs similar to grapes/raisins
3) Grapes contain high levels of tartaric acid/
potassium bitartrate
◦ Levels vary with type, growing conditions, and
degree of ripeness
Other toxins suspected to be present in
grapes/raisins
◦ Ochratoxin, flavonoids, polyphenols, tannins, and
monosaccharides
Grape toxicity ADME:
Grapes toxicosis has _______ onset
◦ This suggests _______ absorption
A clear ______-________ relationship has not been established
◦ This may suggest variation in the number of toxic _________ or varying ________ among individual dogs
Excretion is thought to be ______
Grapes toxicosis has rapid onset
◦ This suggests rapid absorption
A clear dose-response relationship has not been established
◦ This may suggest variation in the number of toxic principles or varying sensitivities among individual dogs
Excretion is thought to be renal
What is the MOT of grape toxicity?
The mechanism of toxicity of grapes/raisins toxin(s) is(are) unknown but…
◦ The injury is mainly on proximal renal tubular epithelium due to a nephrotoxic agent
◦ It could be an idiosyncratic reaction resulting in hypovolemic shock and renal ischemia
◦ The severity of the toxicosis is variable
Can be explained by the variability in the levels of
tartaric acid and potassium bitartrate in grapes with type, growing conditions, and degree of ripeness
What are the clinical signs of grape toxicity?
Vomiting occurs within ___-___h of the ingestion of grapes/raisins
◦ Vomiting could be due to direct effect of the toxins on the ____ ______ or from _______ secondary to renal failure
Subsequently there is ?
_____ and ________ levels increase within 24 hours and remain elevated for days after ingestion of grapes/raisins
3? are seen
Elevated _______ (?) × _______ (?) product
Slightly elevated _______ to ______ ratio
Once _____ renal failure develops, most dogs die or are euthanized
Vomiting occurs within 6-12h of the ingestion of grapes/raisins
◦ Vomiting could be due to direct effect of the toxins on the GI tract or from uremia secondary to renal failure
Subsequently there is diarrhea, anorexia, lethargy, abdominal pain, weakness, dullness, dehydration, isosthenuria, oliguria/anuria
BUN and creatinine levels increase within 24 hours and remain elevated for days after ingestion of grapes/raisins
Hypercalcemia, hyperphosphatemia and hyperkalemia are seen
Elevated calcium (Ca) × phosphorus (P) product
Slightly elevated calcium to phosphorus ratio
Once anuric renal failure develops, most dogs die or are euthanized
How do you Dx grape toxicity?
History of exposure
Clinical signs and histopathological lesions
How do you Tx grape toxicity?
- Handle ______________
- _____________ immediately
◦ _______- (for recent ingestions), gastric ______-, __________ _________. Emesis may be warranted for ingestions >____h because grapes remain in the stomach for some time
◦ Treatments to combat renal failure: ? - Symptomatic therapy: _________ for vomiting
- Supportive therapy: Give IV ______-
◦ Monitor ______ venous pressure (BP in _______ _____ ______-) and ______ production for potential fluid overload
◦ Monitor serum chemistry for indications of
________.
- Handle aggressively
- Decontaminate immediately
◦ Emesis (for recent ingestions), gastric lavage, activated
charcoal. Emesis may be warranted for ingestions >2h
because grapes remain in the stomach for some time
◦ Treatments to combat renal failure: Furosemide,
dopamine, mannitol, hemodialysis/peritoneal dialysis - Symptomatic therapy: Antiemetics for vomiting
- Supportive therapy: Give IV fluids
◦ Monitor central venous pressure (BP in anterior vena cava) and urine
production for potential fluid overload
◦ Monitor serum chemistry for indications of
acute renal failure
List the sources of Amphotericin-B.
antifungal agent (Fungizone, Amphotec, AmBisome). Used for Tx candidiasis, aspergillosis, histoplasmosis
___________ is the major factor limiting the clinical use of Amphotericin-B
Nephrotoxicity is the major factor limiting the clinical use of Amphotericin-B
Amphotericin-B ADME:
_____ oral absorption, _______ bound (___-___%) to plasma proteins, ________ eliminated in urine and bile (detected in urine up to ___ weeks after Tx)
Poor oral absorption, highly bound (90-95%) to plasma
proteins, slowly eliminated in urine and bile (detected in urine up to 7 weeks after Tx)
Which species are susceptible to Amphotericin-B?
all. Cats are the most sensitive
What is the MOT of Amphotericin-B?
Causes renal arteriolar ____________ –> ________ in renal blood flow and ____ –> ______ renal injury –> _______
Forms __________ pores –> renal tubular dysfunction with _________ permeability
◦ _______ monovalent ions delivered to _____ tubule –> _______ GFR via tubuloglomerular feedback mechanism
________ anti-diuretic hormone –> impairment of urine ________ ability –> ______
Causes renal arteriolar vasoconstriction –> reduction in renal blood flow and GFR –> ischemic renal injury –> uremia
Forms intramembranous pores –> renal tubular dysfunction with increased permeability
◦ Excess monovalent ions delivered to distal tubule –> decreased GFR via tubuloglomerular feedback mechanism
Antagonizes anti-diuretic hormone –> impairment of urine concentrating ability –>
polyuria
What are the clinical signs of Amphotericin-B toxicity?
Renal signs: acute renal failure
◦ Polyuria, oliguria or anuria
◦ Hematuria, proteinuria, increased number of casts in urine sediments, ^ BUN, ^ creatinine
◦ Fever, depression, anorexia, nausea, vomiting, diarrhea and anemia
What are the risk factors of Amphotericin-B toxicity?
dehydration and pre-existing renal disease
How do you Tx Amphotericin-B toxicity?
____________ administration of the drug
Provide aggressive ______ therapy to prevent
further renal damage
◦ _______ increases elimination of amphotericin B
Monitor _____, total _____, _____ and serum _____
◦ Stop therapy if _____ becomes abnormal
Discontinue administration of the drug
Provide aggressive fluid therapy to prevent
further renal damage
◦ Mannitol increases elimination of amphotericin B
Monitor PCV, total protein, BUN and serum creatinine
◦ Stop therapy if BUN becomes abnormal
List three examples of Aminoglycosides.
Gentamicin, Kanamycin, Neomycin
What is the MOT of Aminoglycosides?
____________ and ________ esp. in cats. Exact mechanisms are ________
◦ These drugs accumulate in renal ________ tubule cells and __________ of the ear
◦ Result in ________ body (concentric lamellae of phospholipids) formation in ________ of renal tubular cells –> rupture of _______ –> release of ______- –> cell ______
◦ Interact with ribosomes and mitochondria –> impair ______ and _____- synthesis –> cell death
Nephrotoxicity and ototoxicity esp. in cats. Exact mechanisms are unknown
◦ These drugs accumulate in renal proximal tubule cells and endolymph of the ear
◦ Result in myeloid body (concentric lamellae of phospholipids) formation in lysosomes of renal tubular cells –> rupture of lysosomes –> release of enzymes –> cell death
◦ Interact with ribosomes and mitochondria –> impair protein and ATP synthesis –> cell death
What are the clinical signs of Aminoglycoside toxicity?
Renal signs: attributable to acute tubular
necrosis and ARF
◦ Anorexia, vomiting, depression, polyuria,
proteinuria, glucosuria, casts and uremia
What are the risk factors of Aminoglycoside toxicity?
dehydration, duration of therapy, dose, renal disease, age
_____________ is the major factor limiting the use of aminoglycosides
Nephrotoxicity is the major factor limiting the use of aminoglycosides
In a case of Ototoxicosis, there is damage to the cranial nerve ______ –> ______ and ______ dysfunction
In a case of Ototoxicosis, there is damage to the cranial nerve VIII –> vestibular and auditory dysfunction
Defense vestibular dysfunction in a case of ototoxicosis.
nystagmus, incoordination, and loss of righting reflex
Define auditory dysfunction in a case of ototoxicosis
loss of high frequency hearing due to damage to hair cells of the organ of Corti
How do you Tx Ototoxicosis?
Therapeutic monitoring of _______ drug concentration can aid in _______ toxicosis
Discontinue ___________ therapy
________ patient and monitor _______ function
Peritoneal dialysis to remove ______ wastes may be necessary
Therapeutic monitoring of serum drug concentration can aid in preventing toxicosis
Discontinue aminoglycoside therapy
Hydrate patient and monitor renal function
Peritoneal dialysis to remove nitrogenous wastes may be necessary
List the sources of Cholecalciferol (Vitamin D)
◦ Vitamin supplements
◦ Rodenticides
◦ Vitamin D-containing plants e.g., Cestrum spp. (day blooming Jasmine)
Which species are at risk of Vitamin D toxicity?
dogs, cats (more susceptible than dogs), swine, horses
Vitamin D Toxicity ADME:
Readily absorbed following _____ exposure
_____ soluble hence eliminated slowly
Bound to vitamin D-binding protein (?) in plasma
Primary circulating metabolite is _______ which is made in the liver
__________ is activated in the renal proximal tubules to __________
Readily absorbed following oral exposure
Fat soluble hence eliminated slowly
Bound to vitamin D-binding protein (alpha2- globulin) in plasma
Primary circulating metabolite is calcifediol which is made in the liver
Calcifediol is activated in the renal proximal tubules to calcitriol
What is the MOT of Vitamin D toxicity?
Vitamin D enhances plasma Ca2+ and P absorption from the gut by increasing the amount of intestinal Ca2+-binding protein
(calbindin)
It stimulates Ca2+ and P transfer from bone to plasma
It increases renal Ca2+ reabsorption
◦ Acts in conjunction with parathyroid hormone
What are the clinical signs of Vitamin D toxicity?
Result from hypercalcemia and hyperphosphatemia
Involve CNS, muscular, GI, cardiovascular and renal
systems
◦ Depression, vomiting/hematemesis, diarrhea/malena,
constipation, and anorexia
◦ Polyuria, polydipsia, calcuria, and dehydration
◦ Cardiac arrhythmias
◦ Seizures
◦ Mineralization of soft tissue
How do you Dx Vitamin D toxicity?
Rule out other causes of hypercalcemia
History, clinical signs and PM
Serum calcium and phosphorus levels
How do you Tx Vitamin D toxicity?
Decontaminate
◦ _______, _______ ________ and ________ in recently exposed asymptomatic animals.
There is high risk of ________ and _______ during activated charcoal administration
Symptomatic animals
◦ Diuresis with ______ at 2-3× the maintenance rate
_________ to increase renal Ca excretion
________: decreases serum Ca by reducing GI
absorption and increasing renal excretion
Give a ______ to animals whose Ca levels do not respond to therapy
◦ Bisphosphonates lower plasma Ca by inhibiting
bone __________
Decontaminate
◦ Emesis, activated charcoal and cathartic in recently exposed asymptomatic animals.
There is high risk of vomiting and aspiration during
activated charcoal administration
Symptomatic animals
◦ Diuresis with saline at 2-3× the maintenance rate
Furosemide to increase renal Ca excretion
Prednisone: decreases serum Ca by reducing GI
absorption and increasing renal excretion
Give a bisphosphonate to animals whose Ca
levels do not respond to therapy
◦ Bisphosphonates lower plasma Ca by inhibiting
bone reabsorption
How else can you Tx Vitamin D toxicity?
Give salmon calcitonin: lowers plasma ________ by inhibiting _________ activity
◦ Concurrent or sequential use with a ________ is controversial
Supportive care
◦ ________
◦ Give ________ binders, e.g., aluminum hydroxide
◦ Give a low-_________ low-________ diet
Give salmon calcitonin: lowers plasma calcium by inhibiting osteoclastic activity
◦ Concurrent or sequential use with a bisphosphonate is controversial
Supportive care
◦ Hydration
◦ Give phosphate binders, e.g., aluminum hydroxide
◦ Give a low-calcium low-phosphorus diet
March 2007: numerous cases of acute renal
failure in dogs and cats
Melamine (M) and Cyanuric Acid (CA)
List the sources of Melamine
Melamine is primarily used for production of
melamine resins
- E.g. Laminates, adhesives, moldings, plastics,
cleaners, glues, yellow dye, flame retardants
Melamine has been marketed as a fertilizer
because of its high nitrogen content. Was
added to pet food ingredients to fraudulently
increase the apparent protein concentration
Because melamine is 67% nitrogen, based on molecular weight, and protein is
commonly estimated based on the nitrogen content, the addition of melamine
increases the apparent protein content of the food.
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Cyanuric Acid
Found as a co-contaminant with _________
◦ It is an ____________ produced during melamine manufacture and degradation
Used to stabilize _______ in swimming pools and in the manufacturing of bleach, disinfectants, and herbicides
Found as a co-contaminant with melamine
◦ It is an intermediate produced during melamine manufacture and degradation
Used to stabilize chlorine in swimming pools and in the manufacturing of bleach, disinfectants, and herbicides
Oral LD50 in rats: Melamine: 3.16g/kg;
Cyanuric acid: 7.7g/kg
Melamine and cyanuric acid have relatively low
toxicity individually e.g.:
◦ 121 mg/kg melamine is non-toxic to cats
◦ 243 mg/kg cyanuric acid is non-toxic to cats
Toxicity increases dramatically when they are
combined: 32 mg/kg melamine + 32 mg/kg
cyanuric acid is toxic to cats
Melamine and Cyanuric acid toxicity
Well absorbed in the ___ _____ (____-____% in poultry)
Melamine and cyanuric acid undergo minimal
metabolism in __________ animals
Maybe partially metabolized in _________ & _____
The majority of melamine (rats: 90%) or cyanuric
acid (humans: 98%) is excreted __________ in urine
In sheep, 54% is excreted in _______ and 24% in _______
Urinary excretion t½ is 6h in _____ and 4h in _____
Melamine is secreted in _____ and deposited in _____
Well absorbed in the GI tract (90-95% in poultry)
Melamine and cyanuric acid undergo minimal
metabolism in monogastric animals
Maybe partially metabolized in ruminants & poultry
The majority of melamine (rats: 90%) or cyanuric
acid (humans: 98%) is excreted unchanged in urine
In sheep, 54% is excreted in urine and 24% in feces
Urinary excretion t½ is 6h in dogs and 4h in pigs
Melamine is secreted in milk and deposited in eggs
What is the MOT of Melamine and Cyanuric acid toxicity?
Melamine and cyanuric acid cause crystal
formation in renal tubules
Renal injury is hypothesized to result from:
◦ Acute intra-renal obstruction by precipitated crystals
of melamine and cyanuric acid
◦ Combination of factors: inflammation, obstruction by
proteinaceous material secondary to casts, and cell
death
◦ Melamine has diuretic properties and can cause
pre-renal azotemia
Renal tubule occlusion & necrosis
When melamine and cyanuric acid combine, they form a polymer which
precipitates within the renal tubules causing occlusion and necrosis of the renal
tubular epithelium.
In cats that ingested melamine-contaminated food the crystals from kidneys
and urine were found to contain 70% cyanuric acid and 30% melamine.
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What are the clinical signs of Melamine and Cyanuric acid toxicity?
Early signs of toxicosis include depression,
vomiting and anorexia, and are followed by
signs of renal failure
Impaired renal function is characterized by
↑BUN, ↑creatinine, ↑anion gap, polyuria,
polydipsia, and lethargy
Other clinical pathological changes:
hyperkalemia, hyperphosphatemia, and
circular green-brown crystals in urine sediment
Anuria and hematuria have been observed in
children
Describe the pathology of Melamine and Cyanuric acid toxicity.
Bilateral _________
________ in urine
Dark-red band of hemorrhage at the _______ junction
Pale-yellow crystals in renal ________ tubules
Tubular ______ and ______
Interstitial _____ and _______
___ # of inflammatory cells
Bilateral renomegaly
Crystals in urine
Dark-red band of hemorrhage at the corticomedullary junction
Pale-yellow crystals in renal collecting tubules
Tubular necrosis and rupture
Interstitial edema and hemorrhage
^ # of inflammatory cells
How do you Dx Melamine and Cyanuric acid toxicity?
Presence of melamine and cyanuric acid in
food (analyzed by GC/MS and LC-MS-MS )
Presence of melamine and cyanuric acid in
urine or kidney (GC/MS and LC-MS-MS )
Identification of melamine-cyanuric acid
crystals on histopathology or urinalysis
◦ Oil red O stains melamine-cyanuric acid crystals
but not Ca-oxalate or Ca-phosphate crystals
◦ Crystals dissolve over time when kidney
sections are stored in formalin
How do you Tx Melamine and Cyanuric acid toxicity?
Crystalluria is treated with fluid therapy/ increased water intake
◦ Increases urine output and elimination of melamine/cyanuric acid crystals
Alkalinization of urine to reduce formation of melamine-cyanuric acid crystals
Antispasmodic drugs, e.g., atropine have been used to facilitate excretion of uroliths in children
Pain management
