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.
