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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.

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clinically relevant toxicology

Clinically Relevant Toxicology

Tina Wismer DVM, DABVT, DABT

ASPCA Animal Poison Control Center

Urbana, IL

silica gel dessicants
Silica Gel Dessicants
  • Silica is considered chemically and biologically inert
  • Mild GI signs possible
ant and roach baits
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
rodenticides5
Rodenticides
  • Anticoagulants
  • Bromethalin
  • Cholecalciferol
  • Corn-based “Safe” rodenticide
  • Zinc phosphide
anticoagulants mechanism of action
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
Anticoagulant Rodenticides
  • Short-acting
    • Warfarin
    • Pindone
  • Long-acting (second generation)
    • Brodifacoum
    • Bromadiolone
    • Diphacinone
    • Difethialone
    • Chlorophacinone
kinetics
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
Clinical Signs
  • Coagulopathies develop as vitamin K dependent clotting factors are depleted
  • Initially, signs are vague:
    • lethargy
    • exercise intolerance
    • +/- anorexia
clinical signs10
Clinical Signs
  • As signs progress:
    • weakness
    • frank hemorrhage
    • dyspnea
    • bruising
    • lameness
    • seizures
    • death
decontaminate
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
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
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
treatment14
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 and Secondary Toxicity
  • Primary toxicity to all mammals is high
  • Poisoned rodents have killed avian and mammalian secondary consumers

© 2008. ASPCA®

prognosis
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
Bromethalin
  • Vengence®, Assault®, Trounce®, Real Kill®, Sudden Death®
  • Neurotoxin - NOT an anticoagulant!
  • Increasing in popularity and usage
  • Concentration is 0.01%
mechanism of action
Mechanism of Action

Oxidative

phosphorylation

uncoupled

ATP production

Edema of Myelin Sheaths

Loss of Fluid Pumps

toxicity
Toxicity
  • 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 signs20
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
treatment21
Treatment
  • DECONTAMINATION
  • DECONTAMINATION
  • DECONTAMINATION
    • Emesis, activated charcoal (repeated)
  • If clinical signs are present, try to decrease cerebral edema
    • dexamethasone
    • mannitol
    • furosemide
prognosis22
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
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 action24
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
toxicity25
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
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
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
treatment28
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
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
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
prognosis31
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
Zinc Phosphide
  • Arrex®, Commando®, Kilrat®, Gopha-Rid®, Phosvin®, Ridall®, Ratol®, Zinc-Tox®, 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 action33
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
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
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
decontamination36
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?
treatment37
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
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
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
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
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
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
acetaminophen43
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
slide44

Glucuronide

Conjugate

(non-toxic)

APAP

Sulfation

Conjugate

(non-toxic)

Cytochrome

P450

PAP

Hepato-

toxicosis

Methemo-

globinemia

NAPQI

Nephrotoxicosis

acetaminophen dogs
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
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
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
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

Hypothermia

Vomiting

Death

Acetaminophen – Other Clinical Signs

Photos: Robert Russon, DVM

diagnosis
Diagnosis
  • Exposure history
  • Clinical signs
  • Qualitative acetaminophen plasma levels can confirm exposure
    • Human hospital
    • 4 hours post exposure
    • Not sensitive enough for cats
decontamination51
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
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
treatment53
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
treatment54
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
treatment55
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
slide56

APAP

Inhibited by cimetidine

NAT-1—humans, rats, cats (slow)

De-acetylation

NAT-2—humans, rats

PAP

Methemoglobinemia

prognosis57
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
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 action59
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
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
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
ibuprofen toxicity in the cat and ferret
Ibuprofen: Toxicity in the Cat and Ferret
  • Cats
    • Approximately twice as sensitive as the dog
    • Limited glucuronyl-conjugating ability
      • decreased metabolism
  • Ferrets
    • High risk for CNS depression and coma
    • May not have GI upset
ibuprofen chronology
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
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
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
Ibuprofen: Prognosis
  • Good if animal is treated promptly
  • Acute renal insufficiency is usually reversible
  • Liver damage is rare in ibuprofen overdose
other nsaids
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
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
Carprofen (Rimadyl®)
  • Dog
    • GI ulcers 20 mg/kg
    • ARF 40 mg/kg
  • Cat
    • GI ulcers 4 mg/kg
    • ARF 8 mg/kg
nsaid hepatopathy
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
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
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
chocolate73
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
chocolate75
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)
chocolate77
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
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
xylitol79
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
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
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 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
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 therapy84
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 therapy85
Lipid Therapy
  • Ivermectin
  • Moxidectin
  • Calcium-channel blockers
  • Local anesthetics
  • Permethrin
  • Antidepressant medications
  • Baclofen
  • Baytril?
lipid therapy86
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 therapy87
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 therapy88
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 therapy89
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.
slide90

Internet resources

www.aspca.org/apcc