Circulatory Toxins (Lectures 25-28; MT: Polyurethanes-isocyanates, mercury)

What is acetaminophen?

- An analgesic, antipyretic, with some anti-inflammatory properties (indication that it does inhibit COX-2)

When an animal presents with acetaminophen toxicity, what is the first question to ask?

- What is the form/dose/combination/do you have the label?

Which animals are susceptible to acetaminophen toxicity?

- Dogs and cats (Cats > Dogs)

- Ferrets

Acetaminophen toxicities are most commonly:

A. Malicious

B. Intentional

C. Accidental

C. Accidental

Phenazopyridine is metabolized to what?

- Acetaminophen and para-aminophenol

Male or female cats are more susceptible to liver diseases secondary to acetaminophen toxicity?

- Male

Describe absorption and half-life of acetaminophen.

- Rapidly absorbed

- Short half life

Describe the normal metabolism of acetaminophen in the dog.

- Dog: 75% conjugated with glucuronic acid; 20% sulfates, the rest is unchanged and it is excreted in the bile and urine

- Small amount oxidized to reactive intermediate NAPQ1 which gets scavenged by glutathione and excreted in the urine

Describe the normal metabolism of acetaminophen in the cat.

- 90% is sulfonated, 5% cysteine, and 1% glururonidation; the rest is unchanged and it is excreted in the bile and urine.

- Small amount oxidized to reactive intermediate NAPQ1 which gets scavenged by glutathione and excreted in the urine

Describe the metabolism of acetaminophen in overexposure scenarios.

- The detoxification pathways (glucuronidation/sulfonation which is more saturable in cats) are overloaded and more acetaminophen is converted to NAPQ1 and para-aminophenol -> The glutathione supply is depleted -> The remaining NAPQ1 is responsible for hepatic necrosis and para-aminophenol is responsible for methemoglobin formation and RBC lysis

Describe the onset of clinical signs associated with acetaminophen toxicity.

- Delay in onset (<24 hours)

What is the primary, secondary, and tertiary target of acetaminophen toxicity in cats?

- Primary: RBC

- Secondary: Liver

- Tertiary: Kidney (due to hypoxia)

What is the primary, secondary, and tertiary target of acetaminophen toxicity in dogs?

- Primary: Liver

- Secondary: RBC

- Tertiary: Kidney (due to hypoxia)

When you see brown blood you think __________________.

- Methemoglobin

What clinical signs/pathology are associated with acetaminophen toxicity in cats?

- Methemoglobinemia, Heinz body formation, hemolysis, hemoglobinemia/uria which all lead to hypoxemia, hypoxia, weakness, lethargy, tachypnea, and cyanosis

- Liver necrosis leads to salivation, vomiting, abdominal pain, anorexia, Increased liver enzymes/bile acids, decreased protein production, clotting problems, etc.

- All this can lead to convulsions, death (hypoxia - inadequate perfusion, no oxygen; plus liver failure)

- Brown blood

- Mucous membranes can be white or cyanotic or muddy or icteric

- Hypoxia induced renal nephrosis

- Facial/paw edema

What clinical signs/pathology are associated with acetaminophen toxicity in dogs?

- Liver necrosis leads to anorexia, vomiting, depression/lethargy, abdominal pain (more non-specific signs at first) -> icterus, weight loss, increased liver enzymes/bile acids or decreased proteins, clotting problems, etc

- Relative to cats, milder methemoglobinemia, hemolysis, leading to hypoxemia, hypoxia, weakness, lethargy, cyanosis, tachypnea. (higher the dose, more RBC effects you will see)

- Death due to hypoxia and/or liver failure

- Facial/paw edema

- Blood is brown

- Mucous membranes can be white or cyanotic or muddy or icteric

- Hypoxia induced renal nephrosis

What are some differential diagnoses for methemoglobin formation?

- Mothball (naphthalene)

- Drugs

- Oxidant damage (copper/zinc)

- Nitrates in ruminants

- Dried maple leaves/bark in equine and camelids

What are some differential diagnoses for hemolysis?

- Immune mediated

- Allium spp.

- Zinc/copper

- Propylene glycol

- Rattlesnake venom

- Dried maple leaves/bark in equine and camelids

- Pistacia sp. in equines

Broadly, what lesions are associated with acetaminophen toxicity?

- Hepatic necrosis

- Icterus

- Renal nephrosis

- Evidence of hemolysis (moreso in cats)

- Hemoglobin casts

How is acetaminophen toxicity treated?

- Do the math (any exposure is concerning in cats)

- Decontaminate (asymptomatic -> Emetics (<2 hours), AC cathartic, gastric lavage) (Symptomatic -> Often too late, risks v. benefits)

- N-acetylcysteine (sulfhydryl donor which is a precursor for glutathione which binds toxin and decreases methemoglobin formation)

- Ascorbic acid//methylene blue (converts methemoglobin to hemoglobin)

- Supportive (fluids, oxygen, blood transfusion, oxyglobin, liver protectants)

- Monitor liver enzymes every 12-24 hours (good prognostic tool), RBC count every few hours for first 24 hours; If color change to blood is observed -> Monitor for hemolysis for 72 hours)

What is the "antidote" for acetaminophen?

- N-acetylcysteine

What is the prognosis for acetaminophen toxicity?

- Variable (depends on dose and degree of damage)

When you see facial swelling, what should you think about?

- Insect sting

- Snake bite

- Acetaminophen

Glues containing ________________ will expand/foam/cure upon contact with moisture (i.e. in the stomach).

- Polyurethanes (di-isocyanate)

How are ingestions of wood glues/other similar glues treated?

- No emesis

- NPO

- Radiographys/surgery

5 mLs of glue mixed with 5 mLs of water will lead to the formation of what?

- Over 40 mL "glob" within 15 minutes; Will expand at least 3-4 fold, in vitro it will expand 8 fold in 2 hours

Nitrate poisonings are commonly acute or chronic?

- Acute

Which animals are susceptible to nitrate toxicities?

- Ruminants (all species are susceptible to preformed nitrite but it is uncommon to find nitrite sources)

Generally, how do nitrate poisonings occur?

- Ingestion of nitrate accumulating forage (concentrate)

- Any feed (some are worse than others)

- Water (rarely - tends to dilute but will happen under certain circumstances)

What are the major nitrate accumulating plants?

- Amaranthus retroflexus (Pigweed)

- Oat hay

- Chenopodium (Lamb's quarter)

- Sorghum

- Alfalfa

Where in the plant does nitrate accumulate?

- Primarily in the lower stem

What are risk factors for nitrate poisoning in ruminants related to plants?

- Fertilization practices (over fertilization)

- Weather (drought, frost)

- Soil factors/environmental factors

What are risk factors for nitrate poisoning in ruminants related to ruminants?

- High consumption rate

- Lack of adaptation to diet

- Low CHOs

- Older cows

- Pecking order (those that eat first/more)

- Winter/spring months

- "Best cows" (those that eat first/more)

What is the MOA of nitrate poisoning?

- At non-toxic levels in the rumen, nitrate (NO3) is converted to NO2 (nitrite) which is converted to ammonia (dissipates or converted to ammonia)

- At toxic levels, nitrate and nitrite (10x more potent and microflora can't keep up conversion to ammonia) will convert hemoglobin to methemoglobin and metHgb reductase will be overwhelmed and can't convert all the methemoglobin back to hemoglobin

At what level of methemoglobin will clinical signs begin? What are these signs?

- 20-50%

- Signs: Lethargy, dyspnea, salivation, ataxia/tramors/recumbency, pale or cyanotic mms.

At what level of methemoglobin will death occur?

- >70% (will lead to death which is "quiet" or seizures)

If there are animals dead on a farm from nitrate poisoning, if other animals look fine does that mean they are fine?

- No; They may not have received a toxic dose, but it can also have a quick onset/quick recovery

- Look at calcium-magnesium-ptoassium-phosphorus

What are some diagnostic criteria for nitrate toxicity?

- Feed choice (even if they've been on the feed for weeks)

- Abrupt recovery or death (often see dead animals and other are entirely fine)

- Abortions (Delayed)

- Diphenylamine kit for feed

What is the other differential diagnosis (in addition to nitrate) which can cause methemoglobin production in ruminants?

- Chlorate

What samples should be collected to diagnose nitrate toxicity?

- Feed/water (representative sample - can be hot spots)

- Eyeball (enucleate postmortem)

- Serum/plasma (antemortem - only if showing signs)

True or false: GI contents are a good sample to collect for testing for nitrate toxicity.

- False; GIT contents not reliable

How is nitrate toxicity treated?

- Methylene blue IV (converts methemoglobin back to hemoglobin)

- Avoid stress (only go after more seriously affected animals)

- Prevention (test feed/follow guidelines)

- Give feed to monogastrics, return feel, or ensile the feed, or dilute the feed

What are some sources of zinc toxicity?

- US pennies minted starting in 1983

- Canadian pennies from '97 to '01

- Toys

- Miscellaneous (galvanized, zippers, jewelry, pens, tinsel... lots)

- Uncommonly, zinc oxide and zinc salts (zinc acetate, sulfate, gluconate) which are a lower risk -> GI upset

- Zinc sulfate footbaths (LA)

True or false: All forms of zinc are created equal.

- False

What animals are commonly affected by zinc toxicity?

- SA

- Birds

- Zoo animals

- Can technically see in all species

Some zinc containing pennies can pass through the GIT, so why are they still concerning?

- Zinc can leach very quickly from its sources due to gastric acid

Once ingested/absorbed, does zinc tend to accumulate?

- No; Does not tend to accumulate to any great extent chronically; It is excreted in the urine and feces (75% - bile 50%, pancreas 25%)

- Note: Zinc targets its excretory pathways in addition to circulatory system, which is why this is important

Zinc toxicity is more commonly an acute or chronic problem?

- Acute

True or false: All zinc coins pass through the GIT.

- False; sometimes they sit there

What is the toxic dose of zinc?

- Difficult to establish, but we do know that just one penny is a problem

What is the mechanism of toxicity of zinc?

- Overwhelms the excretory pathways and leads to pathophysiology related to excretory pathways and RBCs (oxidative damage -> Acute hemolytic crisis)

What are the three ways anemia can result in a patient?

- Hemolysis

- Loss/comsumption

- Lack of production

Describe the clinical signs and clinical pathology associated with zinc toxicity.

- GIT initially (irritant nature of zinc chloride salt) leading to vomiting, diarrhea, lethargy, anorexia, abdominal pain

- Pale mms

- Regenerative Anemia (pigmenturia, heinz bodies, icterus)

- Renal: Hemoglobin and/or hypoxia and zinc-induced necrosis (azotemia, proteinuria, hemoglobin casts)

- Liver: Increased enzymes and due to zinc and hypoxia

- Pancreas: Increased enzymes due to zinc

- DIC (low risk though)

- Angioedema: Similar to acetominophen

What gross lesions are associated with zinc toxicity?

- GIT inflammation and necrosis

- Tubular necrosis with hemoglobin casts

- Hepatic inflammation and necrosis with pigementation

- Inflammation, necrosis and fibrosis of pancreas

Does a lack of radio-opaque material in a radiograph rule out zinc toxicity?

- No

What are some differential diagnoses to consider in a patient with zinc toxicity?

- IMHA

- Infectious HA

- Allium

- Mothballs (naphthalene)

- Acetaminophen

- Copper

- Snakebite

- Nitrate/nitrites (methemoglobin formation but no hemolysis)

How can a diagnosis of zinc toxicity be confirmed?

- Serum testing

- Liver/kidney/pancreas testing postmortem

How is zinc toxicity treated?

- Remove source (emesis, endoscopy, surgery, manual removal, bulk cathartic)

- Antacids (calcium carbonate, magnesium hydroxide, aluminum hydroxide)

- Hydration, acid/base/electrolyte balance

- Blood transfusions

- Oxygen therapy

- Analgesics, anti-emetics, sucralfate and PPIs for gastroenteritis

- Monitor PCVs frequently

- Chelation therapy (reserved for if the source cannot be removed -> Penicillamine or CaEDTA; No good chelators for zinc, steal from lead and copper)

True or false: All forms of mercury are created equal.

- False

Which types of mercury are more concerning? Which are less concerning?

- Elemental mercury -> Ingestion okay (bulk the diet, GIT protectants, especially if there was glass like with a thermometer, radiographs); Inhalation BAD

- Inorganic mercury -> BAD (severe GIT damage and multi-systemic issues)

- Organic mercury -> BAD (fish/shellfish -> Nervous system signs)

The most common clinical sign associated with rhododendron toxicity is _________________.

- Regurgitation.

What animals are susceptible to anticoagulant rodenticide toxicity?

- All animals can be affected (most commonly dogs)

What are the 5 rodenticides studied in this course?

- Bromethalin

- Strychnine

- Anticoauglant

- Cholecalciferol

- Zinc phosphide

What is a plant source of anticoagulant toxicity in large animals?

- Moldy sweet clover/vanilla grass

- They can also get into treated grain

True or false: All anticoagulant rodenticides are the same.

- False; There are 12 different chemical on the market and while they have the same MOA, they have different half lives (different length of treatment) and different toxic doses (consumer products with more limitations vs. ag professional products)

Which species is relatively resistant to anticoagulant rodenticide toxicity?

- Cats

Most anticoagulant rodenticides are short acting or long acting?

- Long acting (95%) > Short acting

- Assume the animal got into a long acting anticoagulant until proven otherwise

What should be considered in pregnant or nursing animals which ingest anticoagulant rodenticides?

- It can cross the placenta/is secreted in the milk

Are secondary anticoagulant rodenticide toxicity poisonings common?

- No EXCEPT for in "good mousers' or those animals that eat a lot of rodents which is uncommon except for in owls, hawks, raptors

- May also have a residue problem in other wildlife

Most poisonings with anticoagulant rodenticides are...

A. Intentional

B. Malicious

C. Aciddental

B. Malicious

C. Aciddental

What is the MOA of anticoagulant rodenticide toxicity?

- Vitamin K ("active") is an essential co-factor in activation of clotting factors II, VII, IX, and X. Anti-coagulants inhibit the enzyme vitamin K epoxide reductase, which is responsible for recycling "active" vitamin K from "inactive" vitamin K epoxide. There is then a loss of clotting factors and a delayed prolongation of clotting times (in the intrinsic, extrinsic, and common pathways)

Describe the onset of clinical signs associated with anticoagulant rodenticide toxicity.

- Delayed (takes 2-3-5 days)

- Clotting prolongation occurs earlier as early as 12-16 hours, but more commonly at 36-48 hours)

What are some clinical signs associated with anticoagulant rodenticide toxicity?

- Hemorrhage

- Lethargy

- Anorexia

- Dyspnea

- Epistaxis

- Abnormal lung sounds (crackles, wheezes)

- Hemoptysis

- Muffled heart sounds

- Sudden death

After _______% of factors are lost, prolonged clotting times will be noted.

- 65 to 80

The clinical signs, clinical pathology, lesions, and treatment associated with anticoagulant rodenticide toxicities are dependent on what?

- Hemorrhage site

- Speed

- Volume

In 70% of patients with anticoagulant rodenticide toxicity, where does bleeding most commonly occur? What about the other 30% of patients?

1. Lungs

2. Thorax

3. Mediastinum

- Other 30%: bleeding can occur anywhere (signs can vary)

What are some potential clinicopathologic abnormalities associated with anticoagulant rodenticide toxicity?

- Anemia (Don't see it, don't rule this out, Prolonged clotting times will occur first)

- Thrombocytopenia (rare to see < 35k)

- Prolonged PT/PTT/ACT (May not see any changes other than prolonged PT/PTT/ACT (PT first)

- Inflammatory leukogram (nonspecific)

- Regenerative response

- Elevated fibrinogen and FDPs (50%; D-dimers can be elevated)

Hemorrhage associated with anticoagulant rodenticide toxicity commonly occurs in a single site or in multiple sites?

- Can be either

What are some additional diagnostic options for patients suspected of anticoagulant rodenticide toxicity in addition to bloodwork?

- Radiographs (determine source of hemorrhage)

- Tap (run clotting times first; this can be diagnostic but also alleviate distress as in the pericardial sac)

What are some differential diagnoses for prolonged clotting times?

- Anticoagulants

- DIC

- Genetic defect of the common pathway

- Liver disease

- Sulfaquinoxaline (less common)

- Pit viper (less common)

- Malabsorption/lack of vitamin K (rare)

How can anticoagulant rodenticide toxicity be confirmed?

- Blood (clotted/free blood)

- Postmortem Liver sample

True or false: If on necropsy, clotted blood is noted, anticoagulant rodenticide toxicity is ruled out.

- False; It is prolonged clotting, not absence of clotting

How is anticoagulant rodenticide toxicity treated?

1) Decontaminate (even several hours post exposure)

2) Plasma/blood transfusions (if needed) with IV fluids

3) Vitamin K1 (err on the high side with dose) either PO or SQ (PO has better bioavailability but if you gave AC SQ might be a good option) for 4 weeks (takes time to have an effect, at least 12 hours)

4) Supportive (restrict exercise - Trazadone and Gabapentin, oxygen, alfalfa hay in LA)

- Monitor clotting times 36-48 hours after vitamin K1 administration

How does treatment/management of anticoagulant rodenticide toxicity differ for a patient that ingested a toxic dose but is not bleeding?

- Focus on decontamination and administering vitamin K1 (1 and 3 from treatment card)

How does treatment/management of anticoagulant rodenticide toxicity differ for a patient that ingested a toxic dose and has prolonged clotting/evidence of bleeding?

- Focus on transfusions, administering vitamin K1, and supportive care (2,3, and 4 from treatment card)

What is the prognosis for anticoagulant rodenticide toxicities?

- Relatively good with early and aggressive treatment