Lecture 7 - Toxicity Nervous System 2

what species do we often see have salt toxicity?

swine, poultry; rare in cattle or small animal

what is a direct toxicity of salt?

reduced water intake (frozen water, improper water function, medicated water reducing intake)

what is an indirect toxicity of salt?

excess salt in diet

when you have a direct salt toxicity what usually results?

Excessive dehydration → causes increase Na levels in all tissues because water leaves to go into vessels → body naturally tries to balance out the fluid →ingestion of large amounts of water, so excess water now in circulatory (low conc. of salt in blood, high conc, salt in tissues → liquid rushes to brain → edema

when you have indirect salt toxicity, what do you often see?

High salt diet → hypertonic blood → outward fluid movement from brain (tissue) to go into blood to balance salt conc. → dehydration → ingestion of lots of water after body tries to balance out → inward movement of water from hypotonic blood to hypertonic brain → osmotic edema

if cattle were to have direct salt toxicity (horses or grazing animals can have also) what symptoms would you see?

as pressure builds in their brain → instability or seizures or may die

if pigs have indirect salt toxicity, what symptoms do you typically see?

edema, laminar cortical necrosis, and eosinophilic meningoencephalitis. Zone of vacuolation

what can be sources of salt toxicity?

play-doh and paintballs

what are the typical clinical signs of Botulism?

• flaccid muscle paralysis

• progressive motor paralysis

• disturbed vision

• difficulty in chewing or swallowing

• generalized progressive paresis

what are possible sources of Botulinum?

• improperly ensiled small-grain forage (Ryelage, Wheatlage)

• Rotting anything (forage, carcasses)

what happens in waterfowl with botulism toxin?

“limberneck” - flaccid paralysis

what causes Botulism?

Clostridium botulinum

what type of bacteria is Clostridium botulinum?

anaerobic, gram-positive rod

how does C. botulinum metabolize and reproduce?

metabolizes in anaerobic conditions and reproduces via spores that survive in aerobic conditions

what are a common mode of transmission for C. botulinum?

spores

where are the likely places that C. botulinum survive?

soil, intestines, and feces of animals

how do spores likely invade host to cause Botulism?

• most cases is an intoxication, not infection, and results from ingestion of toxin in food

• can enter through seemingly insignificant wounds

what is the usual source of the botulinum toxin?

decaying carcasses or vegetable materials (canning) such as grass, hay, grain, or spoiled silage

what is death usually due to with Botulism?

Respiratory paralysis

what does the specific toxin of botulism prevent?

• motor endplates (neuromuscular junction)

• autonomic ganglia (all muscarinic)

• postganglionic parasympathetic nerves

• postganglionic sympathetic nerves (w/Ach)

what is botulism being used for today?

BOTOX (injected into face, decreased stress less b/c relaxes muscle)

what does the botulinum toxin actually interfere with in the body?

• gets into synaptic cleft

• invades synaptic vesicle to inhibit the SNARE proteins from attaching and pulling vesicle to edge of cleft to release neurotransmitters to cause contraction

• without the SNARE proteins doing their job → no neurotransmitter release → no contraction → get flaccid paralysis

what are early manifestations of Tetanus?

rigidity of the masseter muscles and facial muscles with a distant straightening of the upper lip causing a grimacing posture to the face

what can tetanus cases progress to symptomatically?

frequent localized stiffness near the site of a penetrating wound followed by rigidity of the axial muscles involving the neck, back muscles (opisthotonus) and abdomen

how severe can spasms of tetanus be?

significant enough to break long bones

what other areas of the body can the tetanus spasms affect?

larynx, diaphragm, and intercostal muscles lead to resp failure

since tetanus involves the autonomic nervous system what does it typically result in?

cardiac arrhythmia, tachycardia, and hypertension

what is the biggest concern with tetanus?

resp failure

what is the organism that causes tetanus?

Clostridium tetani

what type of bacteria is C. tetani?

anaerobic, gram positive rod

where does C. tetani metabolize and reproduce?

metabolizes in anaerobic conditions and reproduces via spores that can survive in aerobic conditions

what is a common mode of transmission for C. tetani?

spores

why do people associate a rusty nail with tetanus?

it not because of the rust → b/c its an anerobic environment surrounding the nail so when it cuts it puts the bacteria into the wound → superficial wound closes and becomes a great anaerobic environment for C. tetani to take up shop

where can C. tetani bacteria survive?

same place as C. botulinum (soil, intestine, feces)

what is the incubation for C. tetani?

10-14d, may be several weeks

which species are highly susceptible to C. tetani?

horses, lambs, and people

which species are more resistant to C. tetani?

dogs/cats

which species are highly resistant to C. tetani?

Birds

how is the LD50 (mice) of this toxin measured?

approx. 1ng/kg, making it the second deadly toxin in the world after C. botulinum

what is the pathogenesis of Tetanus?

transported to the spinal cord from the neuromuscular junction and then transported by transcytosis to the inhibitory Renshaw cell and to the upper motor neuron

what does tetanus block?

release of glycine and GABA from inhibitory, leading to spastic paralysis → no relaxation of the antagonistic muscle during normal contraction

what neurotransmitter do botulinum toxins affect more?

acetylcholine

what neurotransmitter do tetanus toxins affect more?

glycine and GABA (synapses)

what is treatment for Tetanus?

• elimination of the source of toxin

• toxin neutralization

• control of muscle rigidity and spasms

• ventilatory support

what specific medications can be given for tetanus treatment?

when administered in the early stages of the dz, curariform agents, tranquilizers, or barbiturate sedatives, in conjunction with 300,000 IU of tetanus antitoxin IV, bid, have been effective in treatment of horses

how can you achieve active immunization for tetanus?

tetanus toxoid vaccine (yearly for animals, every 10 yrs for people)

Locoweed genus names?

Oxytropis, Astralagus

what animals are affected by Locoweed?

cattle, horses, sheep, elk, deer

when is locoweed poisonous?

all times, even when dried

what is the compound in Locoweed that is the toxin?

Swainsonine

what is Swainsonine?

indolizide alkaloid found in all parts of the plants

what does Swainsonine inhibit?

the enzymes alpha-mannosidase I & II

what are the clinical signs with Locoweed?

• sudden changes in temperament, aggressiveness, ataxia, falling over unexpectedly

  • Horses often show more severe neurological effects of locoweed poisoning than cattle and sheep

what is Larkspur?

Delphinium spp.

what is the toxic principle in Larkspur?

Diterpene alkaloids → Methyl-lycaconitine and deactylnudicauline

what are the toxicokinetics of the diterpene alkaloids?

the compounds (methylcaconitine) are readily absorbed from the GI tract and not degraded in the rumen

elimination process of Larkspur?

not well understood

mechanism of toxicity of Larkspur?

compete with acetylcholine binding to the nicotinic receptor at the neuromuscular junction

what does Larkspur produce in the body?

a curare-like, reversible blockade, causing muscle weakness and paralysis (flaccid)

What is Monkshood?

Aconitum spp.

what is the toxic compound in Monkshood?

Polycyclic diterpenoid alkaloids

what are the specific alkaloids found in Monkshood?

aconitine and tetrodotoxin

toxicokinetics of Monkshood?

alkaloids well absorbed, and depending on animal and plant, symptoms usually appear within hours

Mechanism of toxicity of monkshood?

interferes with Sodium channel functions in excitable tissues (prolonged activation)

what is the toxic dose of Monkshood?

0.1%-0.5% of the animal’s body weight

clinical signs of monkshood?

usually begin with paraesthesia, vomiting, diarrhea, and muscle paralysis. Life threatening arrhthymias including ventricular trachycardia and fibrillation, followed by cardiac arrest

what is the MOA of Bromethalin?

uncoupling oxidative phosphorylation in the brain and liver mitochondria

what does Bromethalin result in?

intra-myelin fluid accumulation, leading to long nerve demyelination and intra-myelin cerebral edema

is there an antidote for Bromethalin?

No

what should you do with suspected Bromethalin poisoning?

induce emesis and admin activated charcoal in an asymptomatic animal and controlling CNS signs (seizures) (has to be done early)

what is the MLD for Dog with Bromethalin toxicity?

2.5mg/kg, but death as been reported at dosages of ~1mg/kg in bait

are cats more sensitive or less to Bromethalin than dogs?

2-3 times more sensitive

what are the species of Cyanobacteria?

Anabaena, Aphanizomenon, Microcystis (Annie-Phanny-Mike)

what toxic components to Cyanobacteria have?

Hepatotoxins, Neurotoxins, Dermotoxins, and Endotoxins

what are examples of Hepatotoxins in Cyanobacteria?

• microcystins (tumor promoter)

• Nodularins (carcinogenic)

What are examples of Neurotoxins in Cyanobacteria?

• anatoxin-a (AChE inhibitor, NMB

• saxitoxin (Na channel blocker)