Lecture 24 Flashcards
What is ethylene glycol (EG)?
The chemical found in most automotive ________ _______ products
◦ Not all products have EG: some contain _________ glycol (also toxic)
◦ Antifreeze component in windshield washer fluid most often ________ (also toxic)
Usually comes as _____% EG in undiluted product.
Diluted 50/50 with water in radiator
The chemical found in most automotive radiator antifreeze products
◦ Not all products have EG: some contain propylene glycol (also toxic)
◦ Antifreeze component in windshield washer fluid most often methanol (also toxic)
Usually comes as 95% EG in undiluted product.
Diluted 50/50 with water in radiator
Minimum lethal dose
Dogs
◦ ____-____ ml/kg undiluted
◦ 10 kg dog: ~ 50 ml (~1/4 cup), ~ 25 licks
Cats
◦ _____-____ ml/kg undiluted
◦ 5 kg cat: ~7.5 ml (~ ½ tablespoon)
Dogs
◦ 4.4 - 6.6 ml/kg undiluted
◦ 10 kg dog: ~ 50 ml (~1/4 cup), ~ 25 licks
Cats
◦ 0.9 - 1.5 ml/kg undiluted
◦ 5 kg cat: ~7.5 ml (~ ½ tablespoon)
How does EG taste?
Misconception that EG tastes good? Dogs avoid
EG if other water sources are available
◦ Dec 2012: Antifreeze manufacturers in USA agreed
to add bittering agent
Why does EG poisoning commonly occur?
Most commonly see poisoning if: (i) no other
water source is readily available for thirsty animal,
(ii) puppy chews on product container, (iii) cat
walks through antifreeze spill and grooms self
EG is readily absorbed from the ____ _______
◦ Peak blood conc. ~ __-__ h post-ingestion
◦ ~50% is excreted _________ in urine
◦ ~50% metabolized in ______ to toxic metabolites – a bunch of nasty acid metabolites
Acid metabolites cause metabolic ______ – can be fatal. Also directly injure ____ cells – can be fatal
Calcium in blood & urine combines with ____ ___
◦ Form _______ that precipitate in kidney and elsewhere
◦ Contribute to renal ______
◦ Crystals can be seen ~___ h post-ingestion in dogs and ~___ h in cats
EG is readily absorbed from the GI tract
◦ Peak blood conc. ~ 1-4 h post-ingestion
◦ ~50% is excreted unchanged in urine
◦ ~50% metabolized in liver to toxic metabolites – a bunch of nasty acid metabolites
Acid metabolites cause metabolic acidosis – can be fatal. Also directly injure renal cells – can be fatal
Calcium in blood & urine combines with oxalic acid
◦ Form crystals that precipitate in kidney and elsewhere
◦ Contribute to renal failure
◦ Crystals can be seen ~6 h post-ingestion in dogs and ~3 h in cats
What are the stages of EG toxicosis?
Stage 1: CNS phase
Stage 2: Acidotic phase
Stage 3: Renal failure phase
When do the clinical signs of Stage 1 EG toxicity appear?
◦ ____ min to ____ h post-ingestion
◦ Signs are due to effects of __________ EG
Clinical signs
◦ 30 min to 12 h post-ingestion
◦ Signs are due to effects of unmetabolized EG
What are the CNS signs of Stage 1 EG toxicity?
CNS signs: ataxia/incoordination, inebriation.
Some vomit (due to gastric irritation)
PU/PD, dehydration
◦ Due to osmotic and central effects of EG
(stimulation of the thirst center)
Owners often do not know animal is ill
◦ Clinical signs may be mild in some animals. Some
curl up and sleep it off
How do you Dx Stage 1 EG toxicity?
Ethylene glycol test kits (PRN Pharmacal, Pensacola, FL)
◦ A colorimetric assay to indicate the presence of EG
◦ Can be done on whole blood or serum
Biochemical profile
◦ Increased osmolarity
◦ Phosphorus may be elevated –> Due to ↓GFR and phosphate rust inhibitors added to antifreeze solutions
Urinalysis
◦ Negative at this point
Wood’s lamp
◦ Sodium fluorescein sometimes in antifreeze
◦ Examine urine, vomit, face or paws
EG test kit
EG conc. must be > ____ mg/dL to get positive
◦ Note: ____ can ingest lethal dose and never get a positive
False negative if:
◦ Test too early – not enough ______
◦ Test too late – all EG ________
Best test window: ___-___ h post-exposure
False positive with compounds of _________
structure e.g:?
EG conc. must be > 50 mg/dL to get positive
◦ Note: Cats can ingest lethal dose and never get a positive
False negative if:
◦ Test too early – not enough absorbed
◦ Test too late – all EG metabolized
Best test window: 1-24 h post-exposure
False positive with compounds of comparable
structure e.g:
◦ Propylene glycol
◦ Metaldehyde
◦ Sorbitol
◦ Glycerol
◦ Others
Wood’s lamp
Fluorescein is added to EG to detect leaks
Gives green fluorescence in UV light
What are the principles of treatment of EG toxicity?
Want to ______ EG from going down its metabolic pathway
◦ ___________ production of toxic acid metabolites
Force EG to be excreted ________ in urine
◦ EG is _____ toxic than its metabolites
◦ EG has CNS toxicity similar to ______ but is not
________ and does not cause _________
Want to stop EG from going down its metabolic pathway
◦ Prevent production of toxic acid metabolites
Force EG to be excreted unchanged in urine
◦ EG is less toxic than its metabolites
◦ EG has CNS toxicity similar to alcohol but is not
nephrotoxic and does not cause acidosis
How do you treat EG toxicity?
_________ and __________ may be indicated depending on the stage of the toxicosis. Will discuss the antidotes
Two antidotes are available?
Decontamination and antidote may be indicated depending on the stage of the toxicosis. Will discuss the antidotes
Two antidotes are available:
◦ 4-methylpyrazole (fomepizole; 4-MP)
◦ Ethanol
◦ Use one or the other – NOT both together
4-methylpyrazole (fomepizole, 4-MP)
Fomepizole inhibits ______ so that EG cannot bind with it
◦ A very effective _________ inhibitor of ADH.
ADH has ____-_____x higher affinity for 4-MP than
ethanol
It is the drug of choice in ____, and has been shown to be effective in ____
◦ Dose needed in cats is MUCH _______ than in dogs (e.g., loading dose: 125 vs. 20 mg/kg)
Need to treat _____ after EG ingestion
◦ Best if tx within first __ h in dogs, first ___ h in cats
4-methylpyrazole (fomepizole, 4-MP)
Fomepizole inhibits alcohol dehydrogenase (ADH) so that EG cannot bind with it
◦ A very effective competitive inhibitor of ADH.
ADH has 500-1000x higher affinity for 4-MP than
ethanol
It is the drug of choice in dogs, and has been shown to be effective in cats
◦ Dose needed in cats is MUCH HIGHER than in dogs (e.g., loading dose: 125 vs. 20 mg/kg)
Need to treat SOON after EG ingestion
◦ Best if tx within first 5 h in dogs, first 3 h in cats
Vet product: Antizol-Vet® (Paladin)
◦ FDA approval withdrawn in April 2015 at the
request of manufacturer (Paladin)
No new lot of the drug since October 2014
The last lot of Antizol-Vet sold had an expiry date of
August 2017
◦ Comes as 1.5 g kit for injection. One kit will
treat a 58-lb dog
Human product: Antizol® (Paladin)
◦ Comes as 1 g/mL in 1.5 mL vials
What to do without Antizol-Vet® ?
Use:
◦ Compounded versions
◦ Human-use fomepizole
◦ Ethanol
Note: the manufacturer requested Antizol-
Vet® withdrawal because of low demand
◦ Drug too expensive and not enough profits
Fomepizole
Dogs
◦ Load with 20 mg/kg IV then give 15 mg/kg IV 12 and
24 h post initial dose. At 36 h post initial dose give 5
mg/kg IV. May give additional 5 mg/kg doses if
necessary (until EG test become negative)
Cats
◦ Much higher dose required to inhibit ADH in cats
than dogs.
Load with 125 mg/kg slow IV injection then give q12h
at 31.25 mg/kg IV for 3 treatments
Adverse effects? Almost none
◦ Rare cases of short-duration salivation and tremors
◦ Mild sedation in cats
Ethanol
___________ inhibitor of ADH
◦ Has _____x higher affinity for ADH than EG
Not as effective as _________
MUCH MORE TOXIC than ________
◦ Very ___________ margin of safety
◦ Amount needed to outcompete EG is very close to the ________ dose in dogs and cats
◦ Puts animal into a drunken stupor for __-___ days
◦ Use only if ________ is not available
Competitive inhibitor of ADH
◦ Has 100x higher affinity for ADH than EG
Not as effective as fomepizole
MUCH MORE TOXIC than fomepizole
◦ Very narrow margin of safety
◦ Amount needed to outcompete EG is very close to the lethal dose in dogs and cats
◦ Puts animal into a drunken stupor for 2-3 days
◦ Use only if fomepizole is not available
Ethanol
Note: proof is considered ___X the % of ethanol, e.g., 40% ethanol = ___ proof
2, 80
Stage 2 DX: Urinalysis
Dihydrate (square envelopes)
Monohydrate (picket fence, rods, dumbbells)
How to calculate plasma osmolality
