Week 7-8 - Toxicology Flashcards
What is Bromethalin?
non-anticoagulant rodenticide
Have bromethalin cases increased or decreased over the years?
INCREASED, front runner for most cases
What is ADME?
absorption
distribution
metabolism
excretion
What is the ADME for Bromethalin?
- Toxicokinetic information has largely been derived from experimental studies in rats.
- RAPIDLY absorbed; plasma concentrations peak in about 4 hours.
- Undergoes N-demethylation in the liver, forming des-methylbromethalin, which is thought to be the major toxic metabolite.
- SLOWLY eliminated; its plasma half-life in rats is about six days.
- Parent and metabolite are lipophilic.
- Excretion occurs mainly in bile, and enterohepatic recirculation is likely.
Are dogs or cats more sensitive to Bromethalin? What are the LD50s?
CATS!
*Dog oral LD50 is about 2.38 to 5.6 mg/kg; deaths
have been reported at dosages as low as 1 mg/kg
- Cats are more sensitive with oral LD50 and minimum lethal dosages of about 0.54 mg/kg and 0.4 mg/kg, respectively.
–signs as low as 0.24 mg/kg and 0.75 mg/kg
uniformly fatal.
What is the MOTA of Bromethalin?
- Uncouples oxidative phosphorylation leading to DECREASED CELLULAR ATP production and Na+/K+ ATPase pump failure.
- Loss of osmotic control due to intracellular Na+ retention and secondary water retention (retain sodium, retain water)
- Metabolite, desmethylbromethalin, 2 to 3x more potent.
What is the target organ for Bromethalin?
The BRAIN
CS for Bromethalin intoxication?
DOGS
* < LD50 but more than minimum lethal dose
-Paralytic syndrome beginning with hindlimb weakness and ataxia
-Progressive – up to 2 weeks
-Death due to respiratory failure
-Recovery over several weeks
* > LD50
-Convulsant syndrome within 4 to 36 hours post-ingestion
CATS
* Paralytic syndrome irrespective of dose ingested
* Abdominal distention, ileus, and inability to urinate
* Prior to death: decerebrate posture
not necessarily acute
How do you diagnose Bromethalin intox?
- Detection of metabolite (desmethylbromethalin) in
(descending order):
1) fat
2) brain
3) liver and baits - Postmortem lesions in the brain – can help confirm but the absence of lesions does not rule out toxicosis.
- MRI – will see edema (hyper echoic)
- No typical clinical laboratory
abnormalities
How do you TREAT Bromethalin intox?
- Decontamination
- Control CNS signs
–Diazepam or barbiturate
–Methocarbamol
–Diuretics, mannitol, dexamethasone (not really effective) - Lipid emulsion – since bromethalin is lipophilic
What is the prognosis for Bromethalin intox?
POOR
What does Cholecalciferol (Vitamin D) target?
*Renal
*Cardiovascular
*GI
*Neurologic
Why are we concerned with too much Cholecalciferol?
increase in calcium
main issue is: Metastatic tissue calcification occurs when serum calcium x phosphorous is high.
CS of Cholecalciferol intox?
- Anorexia
- Vomiting
- Diarrhea
- Polyuria/Polydipsia (high Ca – vasopressin –
decrease ability to concentrate urine) - ECG changes
high Ca
high ionized Ca
high phoshporus
high BUN/creatinine
USG - hyposthenuria
How do you DIAGNOSE Cholecalciferol intox?
measure plasma concentrations of the 25-monohydroxy D3 (calcifediol)
How do you TREAT Cholecalciferol intox?
- Decontamination if appropriate
- Monitor serum calcium if asymptomatic
- Hypercalcemic animals
-normal saline IV
-furosemide
-corticosteroids (prednisolone)
-bisphosphonates (many)
–prevents mobilization of Ca from bone
-phosphate binders – aluminum hydroxide
if stop treatment, can have rebound of calcium
monohydroxy cholecalciferol is long lasting
What is an anticoagulant rodenticide?
1st generation:
-Low potency, rapid excretion, short-acting
-Multiple doses required for intoxication
-Common products: warfarin
2nd generation:
-High potency, slow excretion
-Effective after one dosage
-Common products: brodifacoum
will effect blood coagulation – patient can bleed out now
What is the ADME for anticoagulant rodenticides?
*Absorption: slow, but complete
*Distribution: highly bound to plasma proteins,
especially albumin
*Excretion: at various rates, depending on the
compound; major route is via urine
*Plasma half-lives vary between active ingredients
-6 days for brodifacoum in dogs (much longer tissue T1/2)
-14 hours for warfarin in dogs
What are the CS of Anticoagulant rodenticides?
- Site, volume, and rate of hemorrhage determine
the clinical signs - Lag period of 3-5 days, but signs can occur as early as 24 hours post exposure
- Early signs:
-Lethargy, depression, anorexia, dyspnea
-Mouth bleeding, bloody feces, epistaxis,
coughing - Advanced signs:
-Hematomas at traumatized areas
-Irregular heart rate, weak pulse
-Ataxia, convulsions (cerebral hemorrhage) - Sudden death possible
How do you DIAGNOSE Anticoagulant rodenticides intox?
- History
- Clinical signs
- Laboratory parameters:
–CBC, chemistry panel, radiographs
–First: elevated one-stage prothrombin time (PT)
–Second: elevated activated partial thromboplastin time (aPTT) - PIVKA test: proteins induced by vitamin K antagonists
- Detection of anticoagulants in baits, serum, liver; GI contents only useful in recent exposures
What post mortem lesions can you see with anticoagulant rodenticide exposure?
- Generalized hemorrhage (especially in the thoracic and abdominal cavities)
- Pulmonary hemorrhage
- Hemorrhage in the heart
- Hemorrhage in the GI tract
- Liver necrosis from anemia and hypoxia
How do you treat an ASYMPTOMATIC patient with anticoagulant rodenticide exposure?
vomiting, decontamination, vitamin K
- Induce vomiting if within 1-2 hours (maybe
longer) of ingestion - Decontamination with activated charcoal &
cathartic - Vitamin K1 therapy > decision based on exposure assessment and time between exposure and presentation of the patient:
–initiate if decontamination incomplete - If no vitamin K1 therapy:
–Evaluation of clotting parameters should be
performed within 24-48 hours and again at 72-96
hours after exposure
How do you treat a SYMPTOMATIC patient with anticoagulant rodenticide exposure?
- Emergency!
fresh frozen plasma, whole blood, O2, vitamin K therapy
- Provide clotting factors:
–FFP - fresh frozen plasma - If low PCV:
–Whole blood
–pRBC - Oxygen therapy may be necessary
- Vitamin K1 therapy:
–initially 2.5 mg/kg given by injection SQ
–then 2.5 to 5 mg/kg/day given orally for 3-4 weeks
*ICU observation until patient is stabilized
- Cage rest
How do you treat a LACTATING MOM and her babies with anticoagulant rodenticide exposure?
- Pups and kittens possibly at risk
Conservative approach:
* Wean pups and kittens early
* Provide Vitamin K1 to pups and kittens for 2-3 weeks
* Treat bitch or queen with vitamin K1 depending on evidence of coagulopathy
Alternative option:
* Do not wean pups or kittens
* Treat bitch or queen directly while monitoring the
coagulation status of the pups or kittens
What is Strychnine?
non-anticoagulant rodenticide
- Alkaloid obtained from Strychnos
nux-vomica - Generally is a restricted use
rodenticide (RUP).
–baits < 0.5% might be
available
What is the ADME for Strychnine?
*Rapid absorption.
* Significant % is eliminated as parent compound in the urine.
What’s the toxic dose of Strychnine for a dog?
0.75 mg/kg b.w. is a lethal dose
VERY TOXIC - steep dose-response curve
What’s the MOTA of Strychnine?
- Competitively and reversibly antagonizes the inhibitory neurotransmitter, glycine, in the spinal cord and brainstem
- exaggerated reflex stimulation - stiff as a board
- since extensor reflexes more powerful, limb rigidity results
CS of Strychnine
- Rapid onset after ingestion.
- Anxiety, stiffness, “saw- horse” stance
–sensitive to stimuli - Rigidity inhibits respiration; apnea may occur.
- Periods of relaxation become less frequent.
- Death from anoxia (no O2) and exhaustion.
How do you DIAGNOSE Strychnine?
- Clinical signs - pretty dramatic
- Analysis of stomach contents, liver, or urine for
strychnine.
How do you TREAT Strychnine?
- Early: decontamination
–be careful about using emetics due to rapid onset of rigidity
–don’t want to induce vomiting too late bc of unprotected airway - Pentobarbital, diazepam, methocarbamol - lessen rigidity
- Maintain airway – provide oxygen, respiratory support
- Fluids – maintain urine output
- Quiet environment
What is Xylitol?
-a sugar substitute
-5 carbon sugar alcohol: synthetically or
microbially produced
Describe the toxicity of Xylitol
-Dogs appear to be uniquely sensitive.
- Toxic dosages ranged from ~ 1.4 grams/kg to 16 grams/kg for hepatotoxicity.
- Hypoglycemia at dosages as low as 0.15 mg/kg.
What is the MOTA of Xylitol?
-Not known with certainty
-Two hypotheses for hepatotoxicity:
1. depletion of intracellular ATP
2. oxidant-induced damage
-Hypoglycemia associated with a rapid and significant increase in plasma insulin concentrations.
CS of Xylitol exposure
-Emesis, lethargy, coagulopathy
-Elevated serum liver enzyme activities,
hyperbilirubinuria, hypoglycemia,
hyperphosphatemia, prolonged clotting
times, thrombocytopenia
How do you DIAGNOSE Xylitol exposure?
History of exposure and compatible
antemortem signs and clin path changes
and/or postmortem signs/lesions.
Measurement of xylitol in biological samples problematic due to rapid metabolism
What lesions are associated with xylitol?
-Grossly: hemorrhage
-Microscopically: hemorrhage, acute and
severe hepatic necrosis
How do we TREAT xylitol exposure?
- Decontamination
* Emesis
* Not well adsorbed to Activated Charcoal - Treat hypoglycemia
- Treat coagulopathy
* Whole blood
* FFP
* Vitamin K1 - Hepatoprotectants
* Silymarin
* NAC
* SAMe
What is acetaminophen?
-Common OTC household analgesic and antipyretic
–also called paracetamol or APAP
-COX pathway inhibitor (?) – receptors in brain and spinal cord.
What are the toxic doses of Acetaminophen?
-Cats: dosages as low as 10 mg/kg are toxic
cats are more sensitive
-Dogs: 75 to 100 mg/kg
What is the ADME/MOTA of Acetaminophen?
Metabolized in liver as glucoronide or sulfate. Eliminated in urine, intact. 10% is bioactivated to metabolite called NAPQI. Very reactive. Normally conjugated with glutathione then not reactive.
But too much NAPQI – causes damage to hepatocytes.
Why is acetaminophen very sensitive in cats?
-Less efficient at detoxification – can’t glucoronidate
-Less overall capacity to detoxify
-Unique toxic manifestations
-MetHb formation – sensitivity of Hb to oxidation
-less often die due to hepatotoxicity
-Other species – hepatotoxicity of most concern,
but MetHB formation can occur (e.g., dogs > 200
mg/kg)
How do you TREAT acetaminophen exposure?
-Early intervention important
-GI decontamination
-N-acetylcysteine is antidotal
–provides source of cysteine
for glutathione replenishment, improves
efficacy of sulfation pathway, binds directly with NAPQI
–Rate limiting amino acid for glutathione synthesis.
–IV or PO
What is Albuterol?
Drug found in inhalers
selective B2 agonist
Albuterol is a selective B2 agonist – what do B2 agonists do?
-bronchial relaxation
What CS are seen with Albuterol exposure?
- sinus tachycardia
- hypokalemia
What can Albuterol exposure be treated with?
Propanol
What are examples of sleep aids?
often benzodiazepines or non-benzodiazepine hypnotics
-Zolpidem
-Eszopiclone
What’s the MOA of sleep aids?
potentiate GABA transmission, increases frequency of chloride channel opening, and result in inhibition of neuronal excitation
How to you treat sleep aid exposure?
-Early and judicious use of emetics if no CNS effects observed - want protected airway
* AC + cathartic
-animals with liver/kidney disease need baseline labs
-FLUMAZENIL – GABAA receptor antagonist
* should be used only in severe cases and used as needed
-Monitor carefully for seizures
-If paradoxical stimulation do NOT treat with
benzodiazepines!
* phenothiazines or barbiturates are preferred
What is Baclofen?
-muscle relaxant (skeletal muscle)
-mimics GABA
What are the CS of Baclofen exposure?
-CNS and respiratory depression - need ventilator
How do you TREAT Baclofen exposure?
emergency
- Supportive care
-IVF may increase excretion
-atropine
-diazepam
-cyproheptadine (give rectally) - hemodialysis
- Apparent success with intravenous lipid therapy
What are examples methylxanthines?
caffeine, theobromine (chocolate), theophylline
can be from OTC stimulants, Dietary supplements, Foods and beverages
What is the ADME for Methylxanthines?
-Rapid absorption
* theobromine slower than caffeine in dog
-Extensive metabolism in liver
-Enterohepatic recirculation
-Renal elimination
-Caffeine T1/2 vs. theobromine T1/2
* 4.5 hrs. vs. 17.5 hrs.
How toxic is methylxanthins to animals?
-Caffeine and theobromine are acutely toxic to
dogs and cats at ~ 100 to 200 mg/kg.
-Theophylline is acutely toxic to dogs and cats
at 300 mg/kg and 700 mg/kg, respectively.
What is the MOTA of methylxanthines?
-inhibits intracellular Ca sequestration
-competitively antagonizes cellular adenosine receptors
-inhibits phosphodiesterase which results in accumulation of cAMP
-stimulates CNS and cardiac muscle
-promotes diuresis
-induce smooth muscle relaxation
-increase mental alertness, motor activity, and response to normal stimuli–tremors
What are the CS of Methylxanthines?
-target CNS and cardio/heart
-Vomiting and diarrhea
-Restlessness, hyperactivity and hyperreflexia
early
-Muscle twitching, seizures later
-Polyuria
-Tachycardia, tachyarrhythmias and PVCs
-Polypnea/tachypnea
-Hyperthermia
-hypersalivation
What are the CS of Methylxanthines?
-target CNS and cardio/heart
-Vomiting and diarrhea
-Restlessness, hyperactivity and hyperreflexia
early
-Muscle twitching, seizures later
-Polyuria
-Tachycardia, tachyarrhythmias and PVCs
-Polypnea/tachypnea
-Hyperthermia
-hypersalivation
How do you diagnose Methylxanthines?
-History, clinical signs, perhaps vomitus clues
-Detection of alkaloids in tissues, urine or
stomach contents
How do you TREAT methylxanthines?
-Decontamination
* multiple dose AC
-Control seizures
-Treat tachycardia and PVCs
* β-blockers such as metoprolol
*lidocaine
-Urinary catheterization
What are some sources of Ethylene Glycol?
- automobiles
- industrial solvents
- rust removers
- color film processing fluids
- heat exchangers
Are dogs are cats more severely affected from ethylene glycol?
cats, but more cases with dogs
Is the ADME of ethylene glycol slow or rapid?
RAPID, very fast - narrow margin of safety
What’s the toxicity of cats and dogs with ethylene glycol?
cats: 2 to 4 ml/kg
dogs: 4 to 5 ml/kg
Ethylene glycol is metabolized by the ____
LIVER
What is the MOTA of ethylene glycol?
-ehtylene glycol parent – more of a CNS depressant than ethanol – narcotic or euphoric effect.
-Glycoaldehyde – affects cell respiration, alters
glucose and serotonin metabolism, alters amine
concentrations.
-Acid intermediates (glycolate [glycolic acid]) –
metabolic acidosis
-Oxalate + Ca++ = calcium oxalate
-Renal failure 1 to 3 days post-ingestion
What are CS of ethylene glycol exposure?
1-4 hours post:
nausea, emesis, CNS depression, ataxia,
tachycardia, PU/PD, dehydration and hypothermia
3-6 hours post:
severe acidosis, ↑ RR, cardiac conduction
disturbances, coma, convulsions and death
may be delayed for several days:
Oliguric/anuric renal failure
What are some early laboratory findings with ethylene glycol?
-increased anion gap
-osmolar gap (indication of ↑ in osmotically active particles in plasma)
-urine sediment may contain calcium oxalate crystals
-isosthenuria
-hyperphosphatemia
-hyperglycemia
-hypocalcemia
What are some later laboratory findings with ethylene glycol?
-Renal impairment (oliguric renal failure)
* ↑ BUN and creatinine
-hyperphosphatemia - ↓ GFR
-hyperkalemia
How do you DIAGNOSE ethylene glycol?
-Detection of parent EG
-Detection of metabolites
-point of care tests: False + possible: propylene glycol, glycerol, sorbitol
-US - halo kidney
-post-morten lesions: Pale tan, swollen kidneys
How do you TREAT ethylene glycol?
-Decontamination – rapid absorption most
often precludes this.
-Antidotes: ethanol or fomepizole
-Hemodialysis
-Symptomatic and supportive.
* Correct acidosis
* Maintain/establish urine flow
* Monitor serum calcium
How does ethanol and fomepizole help with ethylene glycol exposure?
-Competitively inhibit alcohol dehydrogenase and prevent toxic EG metabolites from forming.
-Fomepizole = more expensive, less side effects
Avoids CNS depression, hypoglycemia,
and dehydration.
Avoids unpredictable metabolism of
ethanol.
More potent and specific inhibitor of liver
alcohol dehydrogenase.
Cost more
Amanitin mushrooms mainly affect which body systems?
liver
What are amanitins?
Most prevalent are α-amanitin and β-amanitin
Amanitins can comprise 0.1% - 0.4% of the weight of an Amanita phalloides mushroom (death cap mushrooms). A single good-sized mushroom is enough to kill an adult person.
NOT DEGRADED by cooking, freezing, or the acidic environment of the stomach
What is the ADME for amanitin mushrooms?
-Use transport system for bile acids to reach hepatocytes
-Enterohepatic cycling maintains high intrahepatocyte concentrations
-Most is eliminated via kidneys 80-90%
-no known metabolism
-Extremely toxic: α-amanitin IV LD50 in
dogs of 0.1 mg/kg (oral LD50s generally
< 1 mg/kg)
What is the MOTA for amanitin mushrooms?
-bind eukaryotic DNA-dependent RNA
polymerase II (RNAP II) which inhibits RNA
elongation essential for transcription
-stop protein synthesis
What are the CS of amanitin mushrooms?
-Long asymptomatic incubation delay following
ingestion - 6 to 12 hours
-Gastrointestinal phase – 12 to 24 hours
–diarrhea, vomiting, abdominal pain and
dehydration
-Hepatotoxic phase – 24 to 48 hours
–liver damage and coagulopathy
-Hepato-renal phase – hemorrhage, convulsions,
fulminant hepatic failure, coma and death
How do amanitin mushroom exposure usually present?
emesis, diarrhea, lethargy, anorexia
What are some clinical pathology findings for amanitin mushroom exposure?
-extremely high ALT (one of highest
was 20,213 U/L)
-Hypoglycemia (lowest was 19 mg/dl)
o liver damage
o affect on insulin secretion?
-Coagulopathy
How would you DIAGNOSE an amanitin mushroom exposure?
-mushroom identification
-ante-mortem: serum, urine, or GI contents for amanitin analysis
-post-mortem: tox testing in liver and kidney
-necropsy: swollen liver, ulcers in stomach, petechiaein lungs
How do you TREAT amanitin mushroom?
*AC
*Antiemetics: metoclopramide,
maropitant
*IV fluids
*Correction of hypoglycemia
*Vitamin K1
*Plasma transfusions
*N-acetylcysteine
*SAMe
*Penicillin G
*Silymarin/Silibinin (Legalon-Sil®)
What toxin does Cycad Palms have?
cycasin
cycad seed needs to be chewed for toxin to be released
What toxin does Cycad Palms have?
cycasin
Leaves, seeds, and roots are toxic; seeds most toxic
cycad seed needs to be chewed for toxin to be released
What does cycsasin of cycads do to the body?
Irritation of GI tract and hepatic necrosis
dogs: signs within 24 hours of
ingestion: vomiting, diarrhea, depression, anorexia, liver failure
What animals are affected by cycads?
dogs, sheep, cattle
How do you TREAT cycad exposure?
-GI decontamination
-activated charcoal
-Supportive and symptomatic care
-GI protectants
-fluids
What toxin is in lilies?
Unknown toxin
Which species is susceptible to lily exposure?
CATS
all parts of lily is toxic
MOTA unknown
What are the CS of lily exposure?
vomiting
depression within 12 hours
transient recovery
Renal failure with initial polyuria then anuria within 2 to 3 days
How do you TREAT lily exposure in cats?
-gastrointestinal tract decontamination
-IV fluid diuresis
-Treatment for acute renal failure
What is the toxin in macadamia nuts?
toxin unknown
MOTA unknown
Which species do macadamia nuts affect?
dogs only
What are the CS of macadamia nuts?
within 12 hours of ingestion:
* MUSCLE WEAKNESS (especially of the hind limbs),
tremors, stiffness
* Depression, vomiting
prognosis: recovering within 48 hours
What is the toxic part of grapes?
Tartaric acid - not present in all grapes
What do grapes cause in dogs?
acute renal failure in dog…
grapes are toxic to cats too!
Some plants contain insoluble calcium oxalates. Why are calcium oxalates bad for cats and dogs?
- Crystals are forcefully ejected when cells are
chewed - Ca-oxalate crystals are sharp and cause mechanical irritation
- During ingestion: Ca-oxalate crystals penetrate oral mucosa, tongue and throat
ALL PARTS OF PLANTS ARE TOXIC
What are CS signs of calcium oxalate ingestion?
- Rapid, within 2 hours of ingestion
– Hypersalivation, head shaking, chewing, pawing at mouth - In severe cases (rare):
-Oropharyngeal edema
-Anorexia, vomiting, depression
-Dyspnea from airway obstruction
How do you TREAT calcium oxalate ingestion?
*Treatment: supportive and symptomatic
Generally treated at home
Flush mouth with water
Yogurt, milk, cottage cheese
*If at DVM:
Flush mouth
Antihistamine to decrease swelling
Fluid therapy
GI protectant: kaolin/pectin, sucralfate
If dyspnea, present to vet clinic immediately
Class signs of opioid intoxication is:
- Depressed mental status
- Decreased respiratory rate
- Decreased tidal volume
- Decreased bowel sounds
- Miotic pupils
What is the MOTA of amphetamines?
-Primary effect: release of catecholamines (dopamine and norepinephrine) from presynaptic terminals. Also serotonergic effect.
-Highly lipid soluble
-Metabolism is minimal; elimination primarily via
urine
-Toxicity: median oral lethal dose in dogs is ~ 9 to
11 mg/kg for methamphetamine hydrochloride
What are CS for cannabis?
-primarily CNS depression
-ataxia
-disorientation
-mydriasis
-urinary incontinence
-also GI signs – emesis
-CNS stimulation in some dogs
-signs may last up to 96 hours
What are the CS fo amphetamines?
Sympathomimetic “Toxidrome”
Hyperactivity
Hypersalivation
Hyperthermia
Mydriasis
Tremors
Hypoglycemia
Tachycardia
Increased blood pressure
Ataxia
Seizures
Repetitive stereotypical behaviors
How do you TREAT amphetamines?
Very early emesis and activated charcoal
IV fluids
control body temp
control tremors (methocarbamol)
control seizure
control tachycardia and hypertension (beta block) AVOID diazepam
protect airway
