4.1 Principles of Tox

Question 1

what is toxicokinetics?

Answer 1

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

Question 2

what is toxicodynamics?

Answer 2

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!

Question 3

what proportion of intoxications show no clinical signs? what about self-limiting signs?

Answer 3

• 57-63% no clinical signs
• 25% self limiting signs

Question 4

if intoxicated animal is coming to the clinic, what should we try to bring with?

Answer 4

Make sure they bring samples
> Source of toxin
 Food, plants
 Container/carton
 Vomitus/feces if available

Question 5

whats the first thing we should do with an intoxicated patient?

Answer 5

 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

Question 6

goals of decontamination?

Answer 6

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

Question 7

goal of detoxification?

Answer 7

Goal: hasten elimination of absorbed toxicant

Question 8

what is the purpose of forced diuresis and what are pros and cons?

Answer 8

Forced diuresis (IV fluids +/- diuretic)
 Toxicants eliminated primarily by kidney
-risk of volume overload
-electrolyte concerns

Question 9

when can we use ion trapping for detoxification? what are the methods we can use?

Answer 9

 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!

Question 10

***what are antidotes?

Answer 10

-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

Question 11

antidote for acetaminophen

Answer 11

N-acetylcystine

Question 12

antidote for anticoagulants

Answer 12

vitamin K1

Question 13

antidote for OP/OC

Answer 13

atropine

Question 14

antidote for ethylene glycol

Answer 14

Fomepizole; ethanol

Question 15

antidote for iron

Answer 15

deferoxamide

Question 16

antidote for cyanide

Answer 16

sodium thiosulfate

Question 17

antidote for lead, arsenic

Answer 17

succimer

Question 18

antidote for amitraz

Answer 18

yohimbine

Question 19

antidote for opioids

Answer 19

naloxone

Question 20

antidote for copper

Answer 20

D-penicillamine

Question 21

what is intravenous lipid emulsion therapy and how does it work? what are its pros and cons? when is it used?

Answer 21

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

Question 22

4 goals of diagnostic toxicology

Answer 22

 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

Question 23

parasympathetic nervous signs

Answer 23

SLUDGE

Question 24

parasympatholytic signs

Answer 24

bloat, dry mouth, mydriasis

Question 25

***List of samples to be collected from live animals that are suspected of being poisoned:

Answer 25

 Whole blood
 Serum
 Urine
 Stomach content
 Feed (if suspect)

Question 26

*** Minimum tissue collection from carcasses should include:

Answer 26

 Liver
 Kidney
 Brain
 Fat
 Urine
 GI content

Question 27

INFO we need to get immediately when a toxicology case is intoduced to us

Answer 27

• 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)

Question 28

***Induction of emesis - at home methods. What use, when, how much, and how to administer? What should we watch out for?

Answer 28

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

Question 29

***contraindications for induction of emesis in animals with poisoning

Answer 29

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

Question 30

***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?

Answer 30

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

Question 31

what is the use of adsorbents for managing intoxications? what is most used? when is it useful? how is it administered?

Answer 31

 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

Question 32

how is activated charcoal formulated? what is the most effective formulation?

Answer 32

 Activated charcoal is formulated as an aqueous slurry, powder or tablets
 Slurries are more effective than tablets or capsules

Question 33

what are some compounds that are not well adsorbed?

Answer 33

• 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)

Question 34

What are some other ways we can prevent absorption of ingested toxins if induction of emesis is not successful, or contraindicated??

Answer 34

-gastric lavage
-gastrotomy and endoscopy
-cathartics

Question 35

what is a gastric lavage? when would we use it and when should we avoid it? how do we administer it?

Answer 35

 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

Question 36

what is the use of gastrotomy or endoscopy when it comes to intoxications?

Answer 36

 Another method of decontamination
 Physical removal of foreign bodies
> Zinc containing pennies
> Galvanized metals/lead
> Button batteries

Question 37

use of cathartics for intoxications? types? how can we use them? what are pros and cons?

Answer 37

 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

Question 38

What are some ways other than ingestion that animals can be exposed to toxic substances?

Answer 38

topical toxins - dermal, ocular

Also consider - inhaled toxins, injected (iatrogenic vs. other)

Question 39

types of topical toxins and how we can avoid them? how can we treat?

Answer 39

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

Question 40

what is LD50? how do we interpret this number?

Answer 40

• 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

Question 41

when is a substance said to undergo enterohepatic circulation?

Answer 41

• 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.

Question 42

what is a good option to treat toxins that undergo enterohepatic circulation?

Answer 42

activated charcoal binds these substances and keeps them in the GI tract

Question 43

what is an antidote?

Answer 43

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

Question 44

why are there species differences for toxins?

Answer 44

• 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.