Transcript No Slide Title

Clinically Relevant
Toxicology
Tina Wismer DVM, DABVT, DABT
ASPCA Animal Poison Control Center
Urbana, IL
Silica Gel Dessicants
♦ Silica is considered
chemically and
biologically inert
♦ Mild GI signs possible
Ant and Roach Baits
♦ Active ingredients: sulfluramid, fipronil,
propoxur, boric acid, and hydramethylnon
 Avermectin, chlorpyrifos, and arsenic
♦ Inert ingredients: peanut butter,
breadcrumbs, sugar, animal fats
♦ Plastic/metal may pose FB hazard
Rodenticides
♦ Commonly
encountered
♦ Accurate identification
required
 Each class unique
♦ Color and formulation
not unique
 Baits come in blocks,
pellets and granules
 Blue, green, red or tan
Rodenticides
♦
♦
♦
♦
♦
Anticoagulants
Bromethalin
Cholecalciferol
Corn-based “Safe” rodenticide
Zinc phosphide
Anticoagulants - Mechanism of
Action
♦
♦
♦
♦
Stops production of clotting factors
Inhibit vitamin K 1,2,3-epoxide reductase
Prevents vitamin K recycling
Affected factors
 II, VII, IX, and X
 extrinsic, intrinsic
and common
coagulation
pathways
Anticoagulant Rodenticides
♦ Short-acting
 Warfarin
 Pindone
♦ Long-acting (second generation)





Brodifacoum
Bromadiolone
Diphacinone
Difethialone
Chlorophacinone
Kinetics
♦ Generally 3-7 days before clinical signs
are seen
 Factor VII has shortest half-life (6.2 hours)
♦ Duration of clinical signs:
 warfarin - 14 days
 bromadiolone - 21 days
 brodifacoum - 30 days (stored in the liver)
Clinical Signs
♦ Coagulopathies develop as vitamin K
dependent clotting factors are depleted
♦ Initially, signs are vague:
 lethargy
 exercise intolerance
 +/- anorexia
Clinical Signs
♦ As signs progress:







weakness
frank hemorrhage
dyspnea
bruising
lameness
seizures
death
Decontaminate
♦ Warfarin
 Decontaminate at 0.5 mg/kg
♦ Second generation
 Decontaminate at 0.02 mg/kg
♦ Emesis
 if less than 4 hours following ingestion
• grain-baits stay in stomach longer
♦ Activated charcoal
 benefit of repeat doses not proven
K1 or not K1, that is the
question
♦ Witnessed or just some evidence
 Chewed package
 Green stools
♦ Age of animal - young are more sensitive
♦ Previous health state
 Concurrent medications
♦ PT at baseline, 48 hours, 72 hour
Treatment
♦ Vitamin K1
 2.5-5 mg/kg/day divided BID-TID PO, IM, SQ
(difference in absorption is only minutes)
 6-12 hours for new clotting factors to be
synthesized
 give with fatty meal to increase absorption
 injectable product may be given orally
Treatment
♦ Emergency needs for clotting factors
(whole blood transfusion, fresh plasma,
fresh frozen plasma)
♦ Oxygen
♦ Restrict exercise/cage rest
♦ Recheck PT 48 hours after last dose of
vitamin K1
Primary and Secondary
Toxicity
♦ Primary toxicity to all
mammals is high
♦ Poisoned rodents
have killed avian
and mammalian
secondary
consumers
© 2008. ASPCA®
Prognosis
♦ Excellent prognosis if treatment started
before clinical signs are evident
♦ If clinical signs are present, prognosis
depends on the type of signs (chest bleed
vs lameness) and severity
Bromethalin
♦ Vengence®, Assault®, Trounce®, Real
Kill®, Sudden Death®
♦ Neurotoxin - NOT an anticoagulant!
♦ Increasing in popularity and usage
♦ Concentration is 0.01%
Mechanism of Action
Oxidative
phosphorylation
uncoupled
Edema of Myelin Sheaths
ATP production
Loss of Fluid Pumps
Toxicity
Acute oral LD50 mg/kg
Norway Rat
2
Mouse
5
Dog
4.7
Cat
1.8
Monkey
5
Rabbit
13
Guinea Pig
>1000
♦ Minimum toxic dose
 literature 1.67 mg/kg
 APCC 0.9 mg/kg
♦ Converted to
desmethylbromethalin
 Several times more toxic
than bromethalin
♦ Half life (dog) = 5.6 days
Clinical Signs
♦ Acute syndrome (doses at or above LD50)
 Signs appear about 10 hours post ingestion
 Mortality rate ~100%
 Agitation, depression, hind limb paresis, tremors,
seizures, death
♦ Chronic syndrome
 Signs may occur 24-86 hours post exposure
 Signs may last up to 12 days
• may fully recover or may have permanent impairment
 Tremors, depression, ataxia, rear limb paresis,
vomiting, recumbency
Treatment
♦ DECONTAMINATION
♦ DECONTAMINATION
♦ DECONTAMINATION
 Emesis, activated charcoal (repeated)
♦ If clinical signs are present, try to decrease
cerebral edema
 dexamethasone
 mannitol
 furosemide
Prognosis
♦ Prognosis varies with severity of
presenting signs
 Asymptomatic or mild depression, ataxia =
good prognosis, recovery in 1-2 weeks
 Severe neurologic signs (coma, paralysis) =
poor prognosis
Cholecalciferol (Vitamin D)
Rodenticides
♦ Mouse-B-Gon®, Rat-B-Gon®, Quintox®,
Rampage®, True Grit®
♦ Marked increase in serum calcium and
phosphorus
♦ Soft tissue mineralization
♦ Renal failure
Mechanism of Action
♦ Cholecalciferol  liver  calcifediol 
kidney  calcitriol (active metabolite)
 increases intestinal absorption of calcium
 stimulates bone resorption of calcium
 increases renal tubular reabsorption of
calcium
Toxicity
♦ LD50 in dogs (technical product)
 88 mg/kg in the dog
♦ Minimum toxic dose in dogs (bait)
 0.5 mg/kg
 Decontaminate at 0.1mg/kg
♦ Juvenile animals and animals with renal
disease may be more sensitive
Cholecalciferol - clinical signs
♦ Early (12-36 h)




Weakness, lethargy, anorexia
Polyuria and polydipsia
Vomiting, often with blood
Increased P (12 h), Ca and azotemia (24 h)
♦ Later signs
 Oliguria and anuria
 Calcification of renal tubules and other highly
vascular tissues and vessel walls
Decontamination
♦ Emesis if ingestion was < 4 hours ago
 decontaminate doses over 0.1mg/kg
♦ Activated charcoal with cathartic
 repeated doses
♦ Baseline (< 8 hours post-exposure) Ca, P,
BUN, creatinine
 Repeat q 12-24 hours, for 4 days
 Goal is Ca x P < 60
Treatment
♦ If Ca (mg/dl) x P (mg/dl) > 60
 soft tissue mineralization may occur
♦ Diurese with 0.9% NaCl
 avoid calcium containing fluids
♦
♦
♦
♦
Furosemide
Prednisolone
Phosphate binder
Low Ca diet
 k/d, u/d, s/d, pasta and lean ground beef
If Ca x P still rising…
♦ Salmon calcitonin
 SQ q 2-3 hours
 Some animals may become refractory
♦ Pamidronate (Aredia®)
 Bisphosphonate, treats hypercalcemia in
people
 Advantages - rapid response, single IV
treatment
 Disadvantages - $$ (now generic), finding it
Treatment - When are you
done?
♦ Normal renal values
♦ Ca X Phos < 60 without ongoing treatment
 Signs may last for 2-4 weeks as calcifediol has a half
life of 16-30 days
Prognosis
♦ Good if caught early
♦ Decreases with prolonged elevations of
Ca and P
 Depends upon the degree of soft tissue
calcification (renal, cardiac, GI)
 Lesions from soft tissue mineralization are
poorly reversible and may result in long term
sequelae or sudden death
• rupture of great vessel several months later, at site
of calcification
Zinc Phosphide
♦ Arrex®, Commando®, Kilrat®, GophaRid®, Phosvin®, Ridall®, Ratol®, ZincTox®, ZP®
 Older rodenticide
♦ Used to kill rats, mice, moles
and gophers
♦ Dark gray, often at 2%-5%
 Paste, tracking powder,
grain-based bait, pellets
Mechanism of Action
♦ Zinc phosphide + water  zinc hydroxide,
phosphine gas
 Unstable in acid environment
 Non-cardiogenic pulmonary edema
♦ If no food in the stomach and phosphine is
not released, intact zinc phosphide can be
absorbed
 damage to liver and kidneys
Zinc Phosphide Toxicosis Signs
♦ Vomiting (if capable of vomiting)
 often with blood
♦ Abdominal pain, ataxia, weakness, leading
to recumbency
♦ Tremors, salivation
♦ Hyperesthesia and seizures
♦ Dyspnea
Chronology and Toxicity
♦ Onset of clinical signs: 15 min. - 4 hours
♦ Lethal dose = 20-50 mg/kg
 cattle, sheep, pigs, dogs, and cats
♦ Species that are able to vomit may
partially self-decontaminate
Decontamination
♦ Emesis - use apomorphine
 NO HYDROGEN PEROXIDE
 Want to keep gastric pH high, don’t feed first
♦ Lavage
 NO WATER
 Aluminum or magnesium hydroxide antacid
♦ Activated charcoal?
Treatment
♦ Seizure control (valium, barbiturates)
♦ Supportive therapy
 IV fluids +/- bicarb (metabolic acidosis)
 n-acetylcysteine via nebulizer
 liver “protectants” (B vitamins, dextrose,
Vitamin C, Vitamin E)
 magnesium (decreases cardiac injury)
 gastroprotectants
Zinc Phosphide - Prognosis
♦ If symptomatic, prognosis is guarded for
24-48 hours
♦ Can see death in 3-5 hours
♦ Monitor liver and kidney for 48 hours
Caution
♦ Phosphine smells like rotten fish or garlic
 If you can smell it, you are being exposed to a
harmful amount
♦ Always have adequate ventilation and
gown, glove and mask when
decontaminating/treating
 Do not wash vomitus down the drain
Unknown Rodenticide
♦ Calculate worst case scenario for each
type of rodenticide
♦ Emesis
♦ Charcoal
 Multiple dose?
♦ PT vs Vitamin K1
♦ Ca, BUN, creat
 Baseline, 24 hours
Unknown Rodenticide Example
Case
♦ Dog 65# ate 0.75 oz of unknown green bait
♦ If bromethalin: 0.07 mg/kg
 No tx necessary
♦ If anticoagulant: 0.03 mg/kg
 Potential problem – emesis, base charcoal and
Vitamin K1 on amount recovered
♦ If cholecalciferol: 0.57 mg/kg
 Serious problem – emesis, charcoal, monitor
bloodwork
Acetaminophen
♦ Analgesic, antipyretic, mild
antiinflammatory
♦ Forms:
 Tablets: 80-650 mg
 Liquid: 32-100 mg/ml
♦ Rapidly absorbed from the GI tract
♦ Peak plasma levels
 10-60 m for regular products
 60-120 m for extended release
Acetaminophen
♦ Formation of reactive metabolites
responsible for toxicity
♦ Metabolites are detoxified by
glucuronidation or sulfation
 Overdose situations saturate pathways
♦ Cats are deficient in glucuronyl sulfatase
 Decreased ability to metabolize APAP
Glucuronide
Conjugate
(non-toxic)
Sulfation
Conjugate
(non-toxic)
Hepatotoxicosis
APAP
Cytochrome
P450
PAP
NAPQI
Methemoglobinemia
Nephrotoxicosis
Acetaminophen- Dogs
♦ Therapeutic dose
 10 mg/kg q 12 h
♦ Toxic Doses
 100 mg/kg - hepatotoxicity
 200 mg/kg - methemoglobinemia
 any dose - KCS (48-72 hr post ingestion)
Acetaminophen - Cats
♦ There is no safe acetaminophen dose for
cats
 10 mg/kg has produced signs of toxicity
♦ Ferrets are as sensitive as cats
Liver necrosis
♦ Depletion of glutathione → hepatotoxicity
♦ NAPQI binds to sulfhydryl groups on cell
membranes
 Central lobular necrosis (cytochrome P-450)
♦ Liver necrosis is less common in cats than
dogs
Methemoglobinemia
♦ Mucous membranes
appear muddy or
brown in color
 accompanied by
tachycardia,
tachypnea, weakness,
and lethargy
Acetaminophen – Other Clinical
Signs
♦ Depression
♦ Facial or paw edema
 More common in cats
Photos: Robert Russon, DVM
♦ Hypothermia
♦ Vomiting
♦ Death
Diagnosis
♦ Exposure history
♦ Clinical signs
♦ Qualitative acetaminophen plasma levels
can confirm exposure
 Human hospital
 4 hours post exposure
 Not sensitive enough for cats
Decontamination
♦ Emesis
 Early
♦ Activated charcoal and cathartic
 Enterohepatic recirculation
♦ Monitor for methemoglobinemia
 Values rise in 2-4 hours, followed by Heinz body
formation
♦ Monitor liver values
 If values are normal at 48 h, no
problems expected
Acetaminophen: Treatment
♦ N-acetylcysteine (Mucomyst®)
 precursor in the synthesis of glutathione
 can be oxidized to organic sulfate needed for
the sulfation pathway
 provides an alternate substrate for
conjugation to reduce the extent of liver injury
or methemoglobinemia
Treatment
♦ NAC is available in 10% and 20%
solutions
♦ Loading dose: 140 mg/kg
 dilute to 5% concentration in 5% Dextrose or
sterile water
♦ 70 mg/kg QID for 7 treatments
 12 to 17 doses
 280 mg/kg loading dose
Treatment
♦ Oral NAC
 nausea and vomiting
 2-3 hour wait between activated charcoal and
PO NAC (activated charcoal will bind)
♦ IV NAC
 also dilute to 5%
 give slow IV over 15 to 20 minutes
Treatment
♦ IV fluids
♦ Oxygen/whole blood/oxyglobin
♦ Ascorbic acid
• helps with reduction of methemoglobin back to
hemoglobin
• questionable efficacy, may irritate the stomach
♦ Cimetidine
• inhibits cytochrome p-450 oxidation system
APAP
Inhibited by cimetidine
NAT-1—humans, rats, cats (slow)
De-acetylation
NAT-2—humans, rats
PAP
Methemoglobinemia
Prognosis
♦ Good if treated promptly
 severe signs of methemoglobinemia or
hepatic damage have poor to guarded
prognosis
♦ Clinical signs of methemoglobinemia may
last 3-4 days
♦ Hepatic injury may not resolve for several
weeks
NSAIDS
♦ Group of drugs
 Different chemical structures
 Similar clinical effects
♦ Popular in vet and human medicine
♦ Most common NSAID call to APCC is
ibuprofen
Mechanism of Action
♦ Inhibit prostaglandin synthesis
 Good:
• decreases pain and inflammation
 Bad:
• decreases secretion of the protective mucous layer
in the stomach and small intestine
• causes vasoconstriction in gastric mucosa
• inhibits renal blood flow - decreased glomerular
filtration rate, decreased tubular ion transport,
decreased renin release
Ibuprofen
♦ Motrin®, Advil®, Midol®, Nuprin®, plus
various combination products
♦ OTC tablets: 50, 100, 200 mg
♦ OTC liquid: 100 mg/5ml
♦ Prescription: 400, 600, 800 mg
♦ Ointment
Ibuprofen: Toxicity in the Dog
♦ Narrow margin of safety
 GI ulcers/perforation in dogs with chronic use at
therapeutic dose of 5 mg/kg
♦ Acute overdose
Dose (mg/kg)
Clinical Signs
50 – 125
175 – 200
400 – 500
> 600
GI (vomiting, diarrhea, nausea, abdominal pain, anorexia)
GI (hematemesis, melena) + renal (PU/PD, rapid onset of oliguria, uremia)
GI + renal + CNS (seizure, ataxia, coma, incoordination, shock)
Lethal dose
Ibuprofen: Toxicity in the Cat
and Ferret
♦ Cats
 Approximately twice
as sensitive as the dog
 Limited glucuronylconjugating ability
• decreased metabolism
♦ Ferrets
 High risk for CNS
depression and coma
 May not have GI upset
Ibuprofen: Chronology
♦ Onset of GI symptoms:
 GI upset: 2-6 hours
 GI hemorrhage/ulceration: 12 hours to 4 days
♦ Onset of Renal failure:
 Usually within 12 hours but may be delayed
until 3-5 days post-exposure
Ibuprofen: Decontamination
♦ Emesis if < 15 minutes
 up to 2 hours if large number of pills (bezoar)
♦ Activated charcoal with cathartic
 repeat dose in 8 hours if large ingestion
♦ GI protectants




misoprostol – synthetic prostaglandin
cimetidine, ranitidine, famotidine - H2 blocker
omeprazole - proton pump inhibitor
sucralfate - gastromucosal protectant
Ibuprofen: Treatment
♦ IV fluids
 2x maintenance for 48 hours (at least)
♦ Monitor BUN, creatinine
 baseline
 repeat in 24, 48, 72 hours
♦ Monitor electrolytes and for acidosis (rare)
Ibuprofen: Prognosis
♦ Good if animal is treated promptly
♦ Acute renal insufficiency is usually
reversible
♦ Liver damage is rare in ibuprofen
overdose
Other NSAIDs
♦ Clinical signs and treatment are the same
as ibuprofen
♦ Toxicity of each NSAID varies between
species
♦ For most NSAIDs the minimum toxic dose
or lethal dose is not established
Naproxen
♦ Naprosyn®, Aleve®, Anaprox®
♦ Extensive enterohepatic recirculation
 prolonged half life (e.g. naproxen 74 hrs in
dogs)
♦ Very high ulcerogenic potential in dogs
 5 mg/kg naproxen
♦ Renal effects 25 mg/kg
Carprofen (Rimadyl®)
♦ Dog
 GI ulcers 20 mg/kg
 ARF 40 mg/kg
♦ Cat
 GI ulcers 4 mg/kg
 ARF 8 mg/kg
NSAID Hepatopathy
♦ Idiosyncratic
 not dose dependent
 thought to be immune-mediated reaction
 very small percentage of dogs affected
• Labradors over represented with carprofen
 can be seen with any NSAID
♦ Signs usually develop in 1st 3-4 weeks,
but can be delayed
Deracoxib (Deramaxx®)
♦ Selective Cox-2
♦ Dog
 GI ulcers 15 mg/kg
 ARF 30 mg/kg
 increased BUN 6 mg/kg/day for 21 days
Chocolate
♦ Toxicosis most common around holidays
 Chocolate season: Halloween to Easter
♦ Methylxanthines
 Theobromine and caffeine
♦ Results in significant CV and CNS
stimulation
♦ Signs may be delayed up to 12 h
Chocolate
♦ Methylxanthine toxicity
 LD50 of caffeine and theobromine ~100-300
mg/kg
 Levels of toxicity:
• 20 mg/kg--mild signs possible
• 40-50 mg/kg—cardiotoxic effects possible
• 60 mg/kg—seizures possible
Compound
Caffeine (mg/oz)
White Chocolate
Theobromine
(mg/oz)
0.25
Milk Chocolate
58
6
Semi-sweet
Chocolate Chips
Sweetened
Cocoa Mix
Unsweetened
Chocolate
Unsweetened
cocoa powder
Cocoa Bean
Mulch
138
22
138
22
393
47
737
70
255
NA
0.85
Chocolate
♦ Emesis
 often successful several hours after ingestion
♦ Activated charcoal
 repeat doses every 6-12 h in symptomatic
animals
♦ IV fluid diuresis
♦ Urinary catheter
♦ Manage arrhythmias prn (propranolol)
Photo courtesy of Dr.
Robert Kessler,
Animal Emergency
Clinic of Las Vegas
Chocolate
♦ Seizure control
 Diazepam, barbiturate or inhalents
♦ Tremor control
 Methocarbamol
♦ Thermoregulation, EKG, electrolytes,
acid/base
♦ Signs may last up to 72 hours
♦ Pancreatitis possible
Xylitol
♦ 5-carbon sugar alcohol
 other sugar alcohols include sorbitol, maltitol
and mannitol
♦ Used in sugar-free chewing gums and
candies and for baking
 anti-cavity, reduces severity of ear infections,
low carb diets, diabetics
♦ Large ingestions cause diarrhea, intestinal
cramping, and hypernatremia
Xylitol
♦ Humans
 Doesn’t significantly raise blood glucose or
significantly stimulate insulin release
 Good alternative to glucose for diabetics
♦ Dogs
 Stimulates insulin release for several hours
 Peak insulin level is dose related
 Changes can be seen at as low as 0.1 g/kg
Xylitol - Clinical Signs
♦ Rapid onset -- signs can be seen within
15-30 minutes
 vomiting, depression, weakness, ataxia,
seizures, coma
 hypoglycemia, hypokalemia
♦ Liver failure
 MOA (decreased ATP production???)
Xylitol - Treatment
♦ Emesis -- only if asymptomatic
♦ Activated charcoal
 Does not bind
♦ Symptomatic dogs




Dextrose -- bolus and CRI
Small frequent meals
Can see prolonged hypoglycemia
Monitor liver enzymes
Lipid Therapy
♦ Lipid emulsion is commonly used as a fat
component for parenteral nutrition
♦ Promising new treatment for toxicosis
♦ Usage based on human research
investigating bupivacaine
♦ Mechanism for lipid rescue
 Possible “lipid sink”
Dosing Protocol
♦ 20% lipid solution
 Peripheral catheter
♦ Initial bolus at 1.5 ml/kg (over 1 minute if
cardiac arrest, slower otherwise) then 0.25
ml/kg/min for 30-60 min
♦ Repeat dose every 4-6 hours if needed
♦ Check for hyperlipemia before repeating
dose
 Redose only if serum clear
Lipid Therapy
♦ General rules of lipophilic drugs:




Are stored in fat
Dissolve in a fat, oil, or non-polar solvent
Readily cross the blood brain barrier
Topically applied medications with systemic
effects
 Passes in milk (more likely to be lipophilic)
Lipid Therapy
♦
♦
♦
♦
♦
♦
♦
♦
Ivermectin
Moxidectin
Calcium-channel blockers
Local anesthetics
Permethrin
Antidepressant medications
Baclofen
Baytril?
Lipid Therapy
♦ While more studies are needed, lipid
therapy is very exciting for lipid soluble
toxicosis (fat-soluble) management
♦ Can hasten recovery time
 Reduced time for intensive care
 Option that may save pet from being
euthanized
• Less $$
Lipid Therapy
♦ Product must be refrigerated
 Open bag is good for 48hrs
♦ Possible complications:





Significant lipemia
Pancreatitis
Transient increased liver enzymes
Volume overload potential
Can also remove antidotes and other
therapies
Lipid Therapy
♦ Relative safety when used IV
 Dosing lower than PPN
♦ Accessible
 Human hospital pharmacies
♦ Inexpensive
 Case of 10-100ml bags $170
 2-year shelf life
Lipid Therapy
♦ Lipidrescue.org
 Website with information and discussions on
lipid administration and treatments
♦ Crandell DE, Weinberg GL. Moxidectin
toxicosis in a puppy successfully treated
with intravenous lipids. J Vet Emerg Crit
Care. Apr 2009; 19 (2): 181-186.
Internet resources
www.aspca.org/apcc
Questions?