Lecture 11: Toxicants of Circulatory & Hematopoietic Systems

What species are sensitive from the fungus fumonisin that comes from improperly stored food sources?

pigs

What is the MOA of fumonisin induced porcine pulmonary edema?

ingestion → inhibits sphingosine N acetyltransferase → increase sphingosine → inhibition of L type Ca channel → decreased myocardial contractility → circulatory back up = left side heart failure and pulmonary edema

What building block molecule is affected by fumonisin?

lipids

Fumonisins have species specific target organ toxicity, what organs are affected in common species?

pigs: lungs

horses: brain

rats, rabbits, sheep: kidney

rats and pigs: esophagus

What is the toxic agent of ergot, also known in humans as St Anthony’s fire?

claviceps purpurea

Where is ergot found?

on grains impacted by certain growing or storage conditions

What are the toxic agents of claviceps purpurea?

• ergonovine

• ergotamine

• lysergic acid amides

• ergopeptines

What is the MOA of ergot toxicity?

act agonistically at biogenic amine receptors in the animal’s body by mimicking them:

• alpha adrenergic (epi)

• serotenergic

• dopaminergic

→ CNS distrubances

What are the clinical signs of ergot toxicity?

• convulsions, hallucinations, paralysis

• abortion, GI disturbance

• gangrene of extremities

• dystocia

How does ergot toxicity cause gangrene of extremities, tissue death , and/or hoof sloughing?

alpha 1 receptors acted on → constriction of smooth muscle in arteries and arterioles → vasoconstriction of peripheral limbs → gangrene etc

What endophyte is responsible for the Kentucky 31 fescue toxicity?

neotyphodium coenophialum

What is the most prevalent ergopeptine, accounting for approximately 90% of the ergopeptine alkaloid content of tall fescue?

ergovaline

What are the clinical effects of fescue toxicity?

• long periods in water due to inability to cool themselves (due to vasoconstriction)

• panting, drooling, heavy respiration

• not eating, not moving, not shedding

• fescue foot → tissue death

What type of tree can be toxic to horses if its wood shavings were used in stalls?

black walnut

What is the toxic component of black walnut trees and what is the MOA?

juglone, a natural phenolic compound, that is absorbed through the coronary band and skin → laminitis

What toxic hematopoietic effect does chloramphenicol have?

bone marrow aplasia

What toxic hematopoietic effect does cephalosporin have?

pancytopenia

What toxic hematopoietic effect does arsenic have?

hemolytic anemia

What is warfarin used for therapeutically?

at low doses in conditions where you have excessive clotting activity or you are trying to prevent clotting; at high doses to block coag cascade → hemophilia type condition

What is the MOA of warfarin?

blocks vitamin K reductase → buildup of oxidized vitamin K (cannot be used in coag cascade)

What is the toxic agent of sweet clover that acts similar to warfarin?

coumarin gets converted to dicoumarol

Warfarin is a _____ generation anticoagulant and therefore requires ______ feeding(s) to result in toxicity.

first; multiple

Diphacinone or cholecaliciferol is a _____ generation anticoagulant and therefore requires ______ feeding(s) to result in toxicity.

second; fewer

What are the toxins found in Allium spp. (onion, shallot garlic)?

organsulfoxides converted to sulfuric acid which chewed

What is the MOA of allium toxicity?

oxidative hemolysis, which occurs when the concentration of oxidants in the RBC exceeds the capacity of the antioxidant metabolic pathways

Why are dogs and cats more susceptible to oxidate damage than the hemoglobin in the other species?

dogs: catalase antioxidant activity in RBCs is low

cats: normal hemoglobin in cats is 2-3x more susceptible to oxidative damage

What is formed in an allium toxicity case when sulfide binds hemoglobin?

heinz bodies

What are some common objects that can cause zinc toxicity?

christmas tinsel, pennies, sunscreen, cages

Why are cats particularly sensitive to acetaminophen toxicity

they lack UDP-glurcuronosyl (an enzyme responsible for a breakdown pathway of acetaminophen) → have to use cytochrome p450 pathway → glutathione gets overwhelmed causing a buildup of toxic benzoquinones

What is the treatment for acetaminophen toxicity and how does it work?

N-acetylcysteine: rejuvinates glutathione to keep pathway open and prevent toxic metabolite formation