4.1 Principles of Tox Flashcards
what is toxicokinetics?
movement of toxicant through the body (ADME)
WHAT DOES THE BODY DO TO THE TOXICANT?
A: ABSORBTION
two most common routes of exposure/absorption are oral/GI and percutaneous/dermal
D: DISTRIBUTION
M: METABOLISM
biotransformation (liver) – making more water soluble for excretion via Phase I and Phase II reactions
bioactivation: nontoxic or low toxic compound to a more reactive metabolite
E: EXCRETION
excretion through feces, urine, exhaled through the breath, sweat it out, in your saliva, excrete through breast milk, etc
what is toxicodynamics?
WHAT DOES THE TOXICANT (OR METABOLITE) DO TO THE BODY?
Dependent on mechanism of action - usually cellular damage, alter structure/function
Bind and activate/block a receptor
Free-radical production
Lipid peroxidation
Alter cell pH
Sometimes we don’t know the mechanism of action!
what proportion of intoxications show no clinical signs? what about self-limiting signs?
- 57-63% no clinical signs
- 25% self limiting signs
if intoxicated animal is coming to the clinic, what should we try to bring with?
Make sure they bring samples
> Source of toxin
Food, plants
Container/carton
Vomitus/feces if available
whats the first thing we should do with an intoxicated patient?
Necessary equipment and emergency meds should be ready for patient
Initial stabilization of the patient should take precedence
> Treat the patient and not the poison!
> A thorough physical exam may be started at this point
goals of decontamination?
Goals: remove source of toxicant, prevent further exposure/absorption (including people - vet, staff, owner)
> This can be achieved through:
Remove source if known
Induction of emesis (vomiting) for recently eaten toxicants
Gastric lavage
Gastrotomy or endoscopic removal
Adsorbents
Accelerate excretion (e.g. use of cathartics)
If the source of the toxin is unknown, consider:
Changing animal location
Changing feed and water
goal of detoxification?
Goal: hasten elimination of absorbed toxicant
what is the purpose of forced diuresis and what are pros and cons?
Forced diuresis (IV fluids +/- diuretic)
Toxicants eliminated primarily by kidney
-risk of volume overload
-electrolyte concerns
when can we use ion trapping for detoxification? what are the methods we can use?
Ideally, the toxicant needs to be:
Excreted unchanged primarily by kidney
Hydrophilic
Not highly protein bound
Alkalinization (pH>7.0) of urine:
Sodium bicarbonate
Trap weak acids, such as ethylene glycol, salicylates
Acidification (pH of 5.5-6.5) of urine:
Ammoniumchloride
Trap weak bases, such as strychnine, amphetamines
=>Questionable efficacy!
***what are antidotes?
-antidotes are agents with specific action against a toxicant
>chemical (neutralize toxin) vs pharmacologic (antagonize effects of toxin)
>many toxins do NOT have specific antidotes
> Cost may be an issue
> Veterinary clinics do not stock many antidotes
Check local hospital; compounding pharmacy
antidote for acetaminophen
N-acetylcystine
antidote for anticoagulants
vitamin K1
antidote for OP/OC
atropine
antidote for ethylene glycol
Fomepizole; ethanol
antidote for iron
deferoxamide
antidote for cyanide
sodium thiosulfate
antidote for lead, arsenic
succimer
antidote for amitraz
yohimbine
antidote for opioids
naloxone
antidote for copper
D-penicillamine
what is intravenous lipid emulsion therapy and how does it work? what are its pros and cons? when is it used?
Intravenous lipid emulsion therapy:
First successful use in humans in 2006, first successful use in a puppy in 2009
Triglycerides derived from plant oils, eggs, glycerin
High margin of safety, list of toxicoses it can help treat is continually expanding
“lipid shuttle”
Consult animal poison control center or veterinary toxicologist if unsure
Adverse effects are infrequent:
Pancreatitis, hemolysis, facial pruritus, pain if extravasation occurs
Reserve for severe intoxications unresponsive to more traditional therapy, or where euthanasia being considered
4 goals of diagnostic toxicology
Form a list of differentials based on the clinical signs and/or lesions
Identify potential sources of the toxicant
Find evidence of exposure to the toxicant
Find evidence of absorption of the toxicant
-often all 4 goals cannot be met and a presumptive diagnosis must be made
parasympathetic nervous signs
SLUDGE
parasympatholytic signs
bloat, dry mouth, mydriasis
***List of samples to be collected from live animals that are suspected of being poisoned:
Whole blood
Serum
Urine
Stomach content
Feed (if suspect)
*** Minimum tissue collection from carcasses should include:
Liver
Kidney
Brain
Fat
Urine
GI content
INFO we need to get immediately when a toxicology case is intoduced to us
- who (animal species, breed, sex, age, weight, medications, etc)
- what (identify source and exposure, original container found?,
potential route of exposure, etc) - when (timelines for exposure, when did it occur, when did clinical signs start)
- where (assess environment, can the animal roam outside, etc)
***Induction of emesis - at home methods. What use, when, how much, and how to administer? What should we watch out for?
Consider if trip to clinic is >1h
>Safest emetic is hydrogen peroxide (3%)
> ~2 mL/kg; 50 mL (large dog), 10 mL (cats)*** > Can repeat 1x in 10-15 min if no success
Inconsistent results; gastric irritation
Caution: aspiration of foam
***Much safer to try in dogs than cats, in cats this is very much a last ditch effort
________________—–________________
NO LONGER RECOMMENDED
Syrup of ipecac (OTC)
~3mL/kg in cats; effective
1-2 mL/kg dogs…..less effective
Bitter tasting
May repeat once in 15 min
Gastric lavage if no vomiting as it can be cardiotoxic
***contraindications for induction of emesis in animals with poisoning
Emesis should not be induced
If the animal:
-has already vomited
-is very drowsy or unconscious
-is exhibiting seizure activity
-has reduced cough reflex
-has an underlying condition which predisposes them to aspiration (eg. megaoesophagus, laryngeal paralysis)
If the substance ingested:
-is likely to cause rapid onset of drowsiness or seizures
-contains paraffin, petroleum products or other oily or volatile organic products which could be aspirated into the lungs
-contains detergent compounds, which could be aspirated into the lungs
-is a strong acid or alkali, which could cause further damage to the oesophagus if regurgitated
Or if it has been >3 hours since ingestion
***how can we induce emesis at the clinic? what percentage of GI contect will we retrieve? what drugs can we use and in what species? what doses? pros and cons?
Emesis generally yields ~50-75% content of upper GI tract
Apomorphine (Dogs)
Not recommended for cats
0.02 to 0.04 mg/kg intravenous (IV) or intramuscular (IM).
> It can also be administered by placing it directly behind the eyelid in the subconjunctival sac.
> Activates dopamine receptors in CNS
CNS/respiratory depression possible with multiple/overdose
Reverse with naloxone
Xylazine (Cats) (or other alpha-2 adrenergic agonist like dexmedetomidine)
0.44 mg/kg IM for xylazine
Adverse effects: sedation, bradycardia
Reverse with yohimbine/atipemazole
what is the use of adsorbents for managing intoxications? what is most used? when is it useful? how is it administered?
Adsorbent most used in veterinary medicine is activated charcoal
> finely powdered material that has been treated to give it a huge surface area (1000
m2/g), which is capable of binding a variety of drugs and chemicals
AC is formed from various carbon sources including peat, wood, or coconut
AC should be used:
> Situations with high suspicion of ingested toxicant; toxicant identified or not!
=> As soon as possible after toxicant ingestion
> Ideally, as soon as possible after emesis or gastric lavage
=> Loading dose of 1-2 g/kg AC
=> Follow up doses of 0.25-0.5 g/kg q 1-6 hrs; may use for 1-3 days duration
how is activated charcoal formulated? what is the most effective formulation?
Activated charcoal is formulated as an aqueous slurry, powder or tablets
Slurries are more effective than tablets or capsules
what are some compounds that are not well adsorbed?
- Acids
- Alkalis (e.g. sodium hydroxide)
- Alcohols (e.g. ethanol, isopropanol, methanol)
- Essential oils (e.g. tea tree oil)
- Glycols (e.g. ethylene glycol)
- Metals (e.g. iron, lead, mercury)
- Petroleum distillates (e.g. turpentine substitute (white spirit), petrol, kerosene)
- Sodium chloride (salt)
What are some other ways we can prevent absorption of ingested toxins if induction of emesis is not successful, or contraindicated??
-gastric lavage
-gastrotomy and endoscopy
-cathartics
what is a gastric lavage? when would we use it and when should we avoid it? how do we administer it?
GL can be used when gastric evacuation is called for but emesis is ineffective/contraindicated
> Avoid GL with caustic/corrosive agents
> Avoid GL with volatile agents
> Avoid GL with sharp objects
Only effective within 1 hr of ingestion
Requires anesthesia, protect airways
Place tube and pump tepid water or saline into stomach, withdrawal by gravity or pump
what is the use of gastrotomy or endoscopy when it comes to intoxications?
Another method of decontamination
Physical removal of foreign bodies
> Zinc containing pennies
> Galvanized metals/lead
> Button batteries
use of cathartics for intoxications? types? how can we use them? what are pros and cons?
Used to hasten elimination of ingested toxins in feces
> Saccharides or saline
> Some AC formulations contain cathartics, eg. Toxiban®
Generally limit activated charcoal (AC) preps with cathartics to one use, then AC-only preps
> Can cause diarrhea and/or dehydration
> Contraindicated in patients with ongoing diarrhea/dehydration
> Caution in young/old patients
Mineral oil used more commonly in horses
> Can assist with elimination of oil-based toxicants in small animals
> Caution with aspiration
What are some ways other than ingestion that animals can be exposed to toxic substances?
topical toxins - dermal, ocular
Also consider - inhaled toxins, injected (iatrogenic vs. other)
types of topical toxins and how we can avoid them? how can we treat?
Wear protective clothing!
Dermal toxins (insecticides, paints, oils)
Mild shampoo baths – repeat, as necessary
If pet not alert, then perform at clinic
AC is recommended for many topical toxins
Excessive grooming by some animals
Enterohepaticrecirculation
Oily substances more challenging
Degreasers/multiple baths
Ocular toxins
Copious flushing of eye (saline)
Topical anesthetics/sedatives may be needed
Treatment of corneal ulcers or uveitis
what is LD50? how do we interpret this number?
- LD50 = median lethal dose/dosage = the dose or dosage required to kill half the members of a tested population after a specified test duration
- a general indicator of a substance’s acute toxicity
- A lower LD50 is indicative of increased toxicity.
– Because you need LESS of the substance to kill half the population of exposed animals
when is a substance said to undergo enterohepatic circulation?
- Substances are said to undergo an enterohepatic circulation (EHC) when they are excreted into the bile, pass into the lumen of the intestine, are reabsorbed and then return to the liver via the circulation.
what is a good option to treat toxins that undergo enterohepatic circulation?
activated charcoal binds these substances and keeps them in the GI tract
what is an antidote?
Antidotes are agents with specific action against a toxicant
Chemical (neutralize toxin) vs. pharmacologic (antagonize effects of toxin)
Many toxins do NOT have specific antidotes
Cost may be an issue
Veterinary clinics do not stock many antidotes
> Check local hospital; compounding pharmacy
why are there species differences for toxins?
- Species differences in toxicant susceptibility are generally related to differences in toxicokinetics
Toxicokinetics: movement of toxicant through the body (ADME)
aka WHAT DOES THE BODY DO TO THE TOXICANT?
eg. The feline liver is generally inefficient at glucuronide conjugation (compared to dogs) and glucuronide conjugation is needed to metabolize permethrin-related substances.
