Lecture 23

Question 1

Name the plants the contain soluble oxalates.

Answer 1

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

Question 2

Soluble Oxalates ADME:
Soluble oxalates are _________ absorbed from the ____
tract and ______ excreted.

Answer 2

Soluble oxalates are rapidly absorbed from the GI
tract and readily excreted

Question 3

Which species are susceptible to Oxalate toxicity?

Answer 3

livestock (most commonly sheep and cattle) and companion animals

Question 4

Label the plants pictured below.
What toxin do these plants possess?

Answer 4

Question 5

What is the MOT of oxalates?

Answer 5

Question 6

What are the clinical signs of oxalate toxicity?

Answer 6

1. Attributable to hypocalcaemia
   ◦ Muscle tremors, tetany, seizures, weakness,
   incoordination, reluctance to move, recumbency,
   depression and coma
   ◦ Rumen atony, bloat, teeth grinding, slobbering
   ◦ Bradycardia
2. Vomiting, ^ BUN and weight loss occur in
   animals that do not die acutely

Question 7

How do you Dx oxalate toxicity?

Answer 7

 History and compatible clinical signs
 Plant identification and occurrence of Ca-
oxalate crystals in kidneys
 Oxalate concentration measured in forage

Question 8

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

Answer 8

 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

Question 9

Lilium and Hemerocallis are also called?

Answer 9

day lily, tiger lily, Easter lily

Question 10

Which species are susceptible to lilium and hemerocallis toxicity?

Answer 10

very toxic to cats (the only known susceptible species)

Question 11

What toxin(s) do lilium and hemerocallis plants possess?

Answer 11

unknown water-soluble toxin. Leaves and flowers
are toxic.

Question 12

What is the toxic dose for lilium and hemerocallis plants?

Answer 12

2-3 leaves are fatal to cats

Question 13

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

Answer 13

 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

Question 14

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 _____

Answer 14

 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

Question 15

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

Answer 15

 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

Question 16

How do you Dx lily toxicity?

Answer 16

 Recognition of exposure
 Clinical signs, clinicopathology and PM lesions
 Serum chemistry and urinalysis

Question 17

How do you Tx lily toxicity?

1. Decontaminate: _______, give ______ ______ and a _______
   ◦ If vomiting has already occurred, give an ____-_____, _____ _______ and a _______
2. Anuric patients
   ◦ Correct ________ and impose fluid diuresis (give __-__ times amount of maintenance fluid)
   ◦ Perform peritoneal _______ or ___________

Answer 17

1. Decontaminate: emesis, give activated charcoal and a cathartic
   ◦ If vomiting has already occurred, give an anti-emetic, activated charcoal and a cathartic
2. Anuric patients
   ◦ Correct dehydration and impose fluid diuresis (give 2-3 times amount of maintenance fluid)
   ◦ Perform peritoneal dialysis or hemodialysis

Question 18

Grapes and raisins come from the genus ______ and raisins (dried grapes with ~ ___% moisture content)

Answer 18

Vitis, 15

Question 19

Which species are susceptible to grape toxicity?

Answer 19

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

Question 20

Which grapes are toxic?

Answer 20

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.

Question 21

What is the toxic dose of grape toxicity?

Answer 21

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

Question 22

What toxins do grapes possess?

Answer 22

 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

Question 23

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 ______

Answer 23

 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

Question 24

What is the MOT of grape toxicity?

Answer 24

 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

Question 25

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

Answer 25

 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

Question 26

How do you Dx grape toxicity?

Answer 26

 History of exposure
 Clinical signs and histopathological lesions

Question 27

How do you Tx grape toxicity?

1. Handle ______________
2. _____________ 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: ?
3. Symptomatic therapy: _________ for vomiting
4. Supportive therapy: Give IV ______-
   ◦ Monitor ______ venous pressure (BP in _______ _____ ______-) and ______ production for potential fluid overload
   ◦ Monitor serum chemistry for indications of
   ________.

Answer 27

1. Handle aggressively
2. 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
3. Symptomatic therapy: Antiemetics for vomiting
4. 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

Question 28

List the sources of Amphotericin-B.

Answer 28

antifungal agent (Fungizone, Amphotec, AmBisome). Used for Tx candidiasis, aspergillosis, histoplasmosis

Question 29

___________ is the major factor limiting the clinical use of Amphotericin-B

Answer 29

Nephrotoxicity is the major factor limiting the clinical use of Amphotericin-B

Question 30

Amphotericin-B ADME:
_____ oral absorption, _______ bound (___-___%) to plasma proteins, ________ eliminated in urine and bile (detected in urine up to ___ weeks after Tx)

Answer 30

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)

Question 31

Which species are susceptible to Amphotericin-B?

Answer 31

all. Cats are the most sensitive

Question 32

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 –> ______

Answer 32

 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

Question 33

What are the clinical signs of Amphotericin-B toxicity?

Answer 33

 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

Question 34

What are the risk factors of Amphotericin-B toxicity?

Answer 34

dehydration and pre-existing renal disease

Question 35

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

Answer 35

 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

Question 36

List three examples of Aminoglycosides.

Answer 36

Gentamicin, Kanamycin, Neomycin

Question 37

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

Answer 37

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

Question 38

What are the clinical signs of Aminoglycoside toxicity?

Answer 38

 Renal signs: attributable to acute tubular
necrosis and ARF
◦ Anorexia, vomiting, depression, polyuria,
proteinuria, glucosuria, casts and uremia

Question 39

What are the risk factors of Aminoglycoside toxicity?

Answer 39

dehydration, duration of therapy, dose, renal disease, age

Question 40

_____________ is the major factor limiting the use of aminoglycosides

Answer 40

Nephrotoxicity is the major factor limiting the use of aminoglycosides

Question 41

In a case of Ototoxicosis, there is damage to the cranial nerve ______ –> ______ and ______ dysfunction

Answer 41

In a case of Ototoxicosis, there is damage to the cranial nerve VIII –> vestibular and auditory dysfunction

Question 42

Defense vestibular dysfunction in a case of ototoxicosis.

Answer 42

nystagmus, incoordination, and loss of righting reflex

Question 43

Define auditory dysfunction in a case of ototoxicosis

Answer 43

loss of high frequency hearing due to damage to hair cells of the organ of Corti

Question 44

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

Answer 44

 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

Question 45

List the sources of Cholecalciferol (Vitamin D)

Answer 45

◦ Vitamin supplements
◦ Rodenticides
◦ Vitamin D-containing plants e.g., Cestrum spp. (day blooming Jasmine)

Question 46

Which species are at risk of Vitamin D toxicity?

Answer 46

dogs, cats (more susceptible than dogs), swine, horses

Question 47

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 __________

Answer 47

 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

Question 48

What is the MOT of Vitamin D toxicity?

Answer 48

 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

Question 49

What are the clinical signs of Vitamin D toxicity?

Answer 49

 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

Question 50

How do you Dx Vitamin D toxicity?

Answer 50

 Rule out other causes of hypercalcemia
 History, clinical signs and PM
 Serum calcium and phosphorus levels

Question 51

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 __________

Answer 51

 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

Question 52

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

Answer 52

 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

Question 53

March 2007: numerous cases of acute renal
failure in dogs and cats

Answer 53

Melamine (M) and Cyanuric Acid (CA)

Question 54

List the sources of Melamine

Answer 54

 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.
3

Question 55

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

Answer 55

 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

Question 56

Oral LD50 in rats: Melamine: 3.16g/kg;
Cyanuric acid: 7.7g/kg

Question 57

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

Question 58

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 _____

Answer 58

 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

Question 59

What is the MOT of Melamine and Cyanuric acid toxicity?

Answer 59

 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

Question 60

Answer 60

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.
4

Question 61

What are the clinical signs of Melamine and Cyanuric acid toxicity?

Answer 61

 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

Question 62

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

Answer 62

 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

Question 63

How do you Dx Melamine and Cyanuric acid toxicity?

Answer 63

 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

Question 64

How do you Tx Melamine and Cyanuric acid toxicity?

Answer 64

 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