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

© 2008. ASPCA®

Primary and Secondary Toxicity

♦ Primary toxicity to all mammals is high

♦ Poisoned rodents have killed avian and mammalian secondary consumers

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

Oxidativephosphorylation

uncoupledATP production

Loss of Fluid PumpsEdema of Myelin Sheaths

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

Acute oral LD50 mg/kg

Norway Rat 2

Mouse 5

Dog 4.7

Cat 1.8

Monkey 5

Rabbit 13

Guinea Pig >1000

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®, 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 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

APAPGlucuronideConjugate(non-toxic)

SulfationConjugate(non-toxic)

CytochromeP450

NAPQI Methemo-globinemia

Hepato-

toxicosis

Nephrotoxicosis

PAP

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

♦ Hypothermia♦ Vomiting♦ Death

Photos: Robert Russon, DVM

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

Methemoglobinemia

PAP

De-acetylation NAT-1—humans, rats, cats (slow)NAT-2—humans, rats

Inhibited by cimetidine

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 Signs50 – 125 GI (vomiting, diarrhea, nausea, abdominal pain, anorexia)175 – 200 GI (hematemesis, melena) + renal (PU/PD, rapid onset of oliguria, uremia)400 – 500 GI + renal + CNS (seizure, ataxia, coma, incoordination, shock)

> 600 Lethal dose

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

♦ 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 Theobromine (mg/oz)

Caffeine (mg/oz)

White Chocolate 0.25 0.85

Milk Chocolate 58 6

Semi-sweet Chocolate Chips

138 22

Sweetened Cocoa Mix

138 22

Unsweetened Chocolate

393 47

Unsweetened cocoa powder

737 70

Cocoa Bean Mulch

255 NA

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?