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Toxicology > 3-Neurotoxicants > Flashcards

3-Neurotoxicants Flashcards

1
Q

Chemicals that cause neurotoxicity

A

Natural and synthetic

  • Clostridium botulinum
  • Strychnine
  • synthetic pesticides

Largest class of chemicals inducing toxicosis

Clinical signs

  • peripheral vs. central
  • excitatory vs. depressive

Differentiate primary effect from secondary effect

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2
Q

Pesticides

A

In use since AD 70

1940s: started makig our own pesticides

  • Organochlorines (DDT)
  • Organophosphates (parathion)
  • Carbamates, dithiocarbamates, synthetic pyrethrins
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3
Q

Rachel Carson

A

Silent Spring

dogs, cats, humans, gators, birds

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4
Q

Organophosphate Pesticides

A

Agricultural and residential use inc

  • Degrade faster
  • Used in flea collars, dips, fly, ant, roach baits

Parathion, Malation, chlorpyrifos

High water solubility and acute toxicity

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5
Q

OPs mechanism of action

A

Irreversible inhibition of acetylchonine esterase (AChE) activity

Cholinergic overstimulation within minutes to hours

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6
Q

Clinical signs of anti-esterase toxicity

A

Muscarinic (SLUDGE-M): DOGS

Nicotinic: CATS

  • muscle fasciculations beg with face, eyelid, tongue
  • generalized tremors, weakness, paralysis

CNS

  • Respiratory depression, ataxia, nervousness, tonic-clonic seizures

Clinical signs may last 1-5 days

  • In acute poisoning
    • primary clinical signs: respiratory distress and collapse, then death due to respiratory muscle paralysis
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7
Q

Muscarinical clinical signs

SLUDGE-M

A

Salivation

Lacrimation

Urination

Defecation

GI

Emesis

Midriasis

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8
Q

Species spec clinical signs OP tox

Horses

Cattle

Cattle and sheep

Dogs and cats

Nicotinic signs in cats

A

Horses show clinical signs of colic and dehydration

Rumen stasis in cattle, but not miosis

Cattle and sheep commonly show severe depression

CNS stimulation in dogs and cats, progressing to convulsions

Chlorpyrifos causes more severe nicotinic signs in cats => muscarinic tolerance

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9
Q

Diagnosing Anticholinesterase Toxicity

A

Appropriate history and clinical signs

Atropine Challenge

  • Administer pre-anesthetic dose (0.01-0.05 mg/kg)
  • wait 15 minutes observe for normal signs of atropine admin
    • dry mouth
    • mydriasis
    • increases heart rate
  • Observation of signs means NO cholinesterase inhibition

Non-specific pathology => not very helpful

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10
Q

Treating Anti-esterase Toxicity

A

GI decontamination, bathing for dermal exposure

  • activated charcoal

Atrophine sulfate for muscarinic signs, dose to effect; will not stop nicotinic signs

  • dose to effect

Oximes (protopam, 2-PAM) can reactivate AChE

  • aging of OP causes non-reversal

Diazepam or baribturates for seizures

Time

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11
Q

Pathology in a dog following OP toxicity

A

Vacuolization of the brain

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12
Q

OPIDN

Organophosphate-induced delayed neurotoxicity

A

OP compounds that produce signifiant inhibition of neuropathy target esterase (NTE)

  • may cause delayed neuropathy

Characterized by axonal degeneration of long motor neurons

  • hindlimb weakness
  • paralysis

No treatment

*Sensory system fine

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13
Q

Ivermectin

A

Produced by a soil fungus: Streptomyces avermitilis

  • toxicosis through GABA receptors

Worm med in cats/dogs

Anthelminthic in livestock

Dogs: 6-24 micrograms/kg HW prev

  • 200 micrograms/kg can cause ataxia, disorientation

Collies, Shepherds, Shelties

  • 80-100 micrograms/kg causes toxicity
  • passes BBB
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14
Q

Ivermectin

MOA

A

GABA-A receptor agonist

  • increases GABA release
  • enhances GABA binding
  • direct GABA receptor agonist

Increased inhibitory input => decreased ability to respond to other stimuli

Long half-life

  • cumulative toxicity
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15
Q

Ivermectin tox

Clinical signs

A

Clinical signs

  • onset time is hours to 1 day
  • CNS depressant
    • ataxia disorientation, lethargy, mydriasis, coma, blindness, some bradycardia
  • recumbency and seizures in collies
  • respiratory distress typically precedes death
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16
Q

Ivermectin tox

Diagnosis

A

History of administration

Brain ivermectin conc > 100ppb

Can also measure in GI content, liver, fat, feces

No visible lesions, no dx BW

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17
Q

Ivermectin tox

Tx

A

Recent exp

  • GI decontamination
  • Multiple doses of activated charcoal

Supportive care

  • fluids
  • electrolyte therapy
  • epinephrin
  • short acting barbituates
  • NO BENZOs

Prognosis

  • non-susceptible breeds: good if exposed to <5 mg/kg
  • Guarded at dosages >5mg/kg any breed

Can test dogs prior to admin higher doses

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18
Q

Other rodenticides that affect CNS

A

Bromethalin: mitochondria inhibitor

  • Single-dose rodenticide
  • Kills in 3-5 days (delay toxicity)
  • Parent and metabolite uncouple oxidative phosphorylation in CNS

Nicotine

  • Usually stimulate then block nicotinic ACh receptor
  • LD50 1-2 mg/kg

Metaldehyde

  • Sources include fuel for small heaters and molluscicides
  • 3-4 oz bait toxic to average sized dog/sheep
  • metabolism to acetaldehyde = CNS excitation
    • acetaldehye: hangovers
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19
Q

Mycotoxins (aflatoxin)

A

Fungal metabolites cause pathological, physiological and/or biochemical alterations

  • usually on several organ systems

Can affect all species

  • peanut butter routinely screened
  • 2004 outbreak in Kenya
  • outbreaks in dog food
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20
Q

Mycotoxin

Slaframine

A

Produced by ‘Black patch’ fungus on red clover

  • rain, high humidity, cool weather triggers growth

ACh mimic

  • primarily acts as a muscarinic cholinergic agonist (esp in exocrine glands)
  • SLUDGE-M

Occurs regularly in Central, south-east, and south-west US

Most common in horses and cattle

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21
Q

Slaframine

Clinical Signs

A

Copious salivation

  • may be only clinical sign

Bloat, diarrhea, frequent urination

Feed refusal

*mild toxicosis

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22
Q

Slaframine

DX

A

Diagnose

  • consumption of clover, ID of black patch in clover

Differentiate from OPs, botulism

23
Q

Slaframine

Treatment

A

Remove source

Maintain hydration, electrolytes

Atropine

Clinical signs cease in 48 hours

rarely fatal

24
Q

Mycotoxin

Fumonisin

A

Metabolite of Fusarium spp (imp toxin is fumonisin B1)

Found almost exlusively on corn

Usually occurs in years of drought followed by wet weather

Presence of Fusarium spp. not indicative of fumonisin

25
Q

Fumonisin

MOA

A

Inhibition of sphingosine-N-acetyltransferase

  • increases levels of sphinganine => cytotoxic

Affects vascular endothelial cells

  • stroke
  • hepatic injury
  • pulmonary edema

Susceptible species: horses, swine, rabbits

26
Q

Two diseases linked to fumonsins

A

ELEM (equine leucoencephalomalacia)

PPE (porcine pulmonary edema)

27
Q

Porcine pulmonary edema

A

First clinical signs

  • inactivity
  • inc resp rate
  • dec heart rate

Signs about 12 hours before development of pulmonary edema

Lethal pulmonary edem occurs within 4-7 days of consuming contaminated feed

Respiratory distress (inc rate, open-mouthed breathing) occurs within hours of death

28
Q

Diagnosis of PPE

A

Analysis of feed for fumonisin (>50ppm) in conjuction with clinical signs

Earliest and most specific biochemical change

  • increase in serum and tissue sphingoid bases

Inc liver enzymes, total bilirubin, bile acids and cholesterol

Post morten pathology

  • pulmonary edema
  • hepatic lesions
  • necrosis

*water in lungs through lymphatics

29
Q

ELEM

(equine leukoencephalomalacia)

A

Most common in late fall/early winter

Main target organ

  • brain
    • acute onset anorexia, ataxia, circling, drowsiness, blindness, progressive hysteria
    • Terminal signs
      • hyperexcitability, mania, profuse sweating
  • liver
    • Jaundice, hepatic encephalophaty
    • Coma and convulsions from hepatic encephalopathy are terminal

Nearly 100% mortality rate

TERMINAL FRENZY: Liquefying brain

30
Q

ELEM

DX

A

Feed analysis (>10ppm) with clinical signs

Severe liver injury and lesions

  • elevated serum cholesterol levels
  • increased liver enzymes
    • ALP
    • ALT
    • sorbitol
    • dehydrogenase
    • GGT and total bilirubin and bile acids

Post-morten

  • CNS necrosis
  • liquefaction
31
Q

Fumonisin tox

TX

A

No Tx

Isolate spastic animals

Change feed

  • pigs usually recover w/in 48 hours of removing contaminated feed

New treatment:

  • Ultrasorb S => species specific mycotoxin deactivator
32
Q

Tremorgenic mycotoxins

A

Fungi of general Penicillum, Aspergillus, Claviceps

  • over 20+ species
  • Elicit intermittent/sustaines tremors in vertebrates
  • Sources
    • food
    • stored grains/nuts
    • forage for livestock
    • garbage
    • compost

MOA: release of neurotransmitters from synaptosomes in CNS

Clinical signs

  • diminished activity and immobility
  • hyperexcitability
  • muscle tremors
  • ataxia
  • tetanic seizures
  • convulsions
33
Q

Ammoniated feed toxicosis

A

NPN (non-protein nitrogen sources)

  • urea
  • ammonium salts

Found in high conc in some mineral licks

affected species

  • bovine
  • caprine
  • ovide

Bovine bonkers

34
Q

Clinical signs of ammonia tox/imidazoles

A

Hyperexcitability

  • nervousness
  • rapid blinking
  • dilated pupils
  • trembling
  • ataxia
  • rapid respiration
  • SLUD
  • tonic convulsions

Imidazole poisoning

  • animals will alternate between hyperexcitability and normal

Onset of clinical signs rapid: 15 min to several hours

  • death within 24 hours
  • when blood ammonia >2 mg/dL
35
Q

Ammonia Toxicosis

DX

A

History of exp

Clinical signs

DDX:

  • OP pesticides
  • cyanide
  • grain overload: ketoacidosis - lactic acid
  • meningitis
  • encephalitis

Analysis of feed/blood/rumen fluid for ammonia

  • normal: <0.5 mg/dl

Inc ammonia, glucose, BUN, decreased blood pH may help dx NPN overdose

36
Q

Imidazole tox

TX

A

No treatment

  • sedation may prevent self-mutilation
  • Milking out cows that have affected calves
  • Prognosis good in adults if feed removed quickly

Feed removal

37
Q

NPN overdose tox

TX

A

No specific treatment

  • 5-10 gallons cold water and 1 gallon vinegar by stomach tube
    • cold reduces urease activity
    • vinegar acidifies rumen to convert ammonia to less absorbable form

Prognosis:

  • poor for recumbent animals
  • good if id’d early
38
Q

Strychnine

A

From seeds of strychnos-nux vomica (Indian tree)

Alkaloid used to control pocket gophers

Restricted use pesticide

often used as a malicious poison

LD50 0.5-3 mg/kg (birds higher)

39
Q

Strychnine

MOA

A

Rapidly absorbed and distributed to blood, liver, and kidney

Rapid elimination

  • complete in 48-72 hours

Competitive antagonist at postysnaptic spinal cord and medulla glycine receptors

  • results in disinhibition (stimulation) of all muscles

Glycine

  • inhibitory transmittor
40
Q

Strychnine tox

Clinical signs

A

Rapid onset 10-120 minutes with little to no vomiting

Begining

  • anxiety
  • restlessness
  • stiff neck and gait
  • facial muscles stiffen => ‘grinning’
  • ears twitch

Proceeds to

  • violent tetanic seizures initiated by external stimuli
  • Progressively more frequent
  • Respiratory distress
  • Sawhorse stance, rigid extension all 4 limbs
  • Death from resp failure (asphyxiation during seizures), exhaustion
41
Q

Strychnine Tox

DX

A

Stim induced tetanic seizures, rigit extension

Hyperthermia in dogs

  • 104-106 F

Chemical analysis of bait, stomach contents, liver

Elevated CPK and LDH in serium

Common lab findings

  • Lactic acidosis, hyperkalemia, leukocytosis

Rule out other things causing seizures

  • OP
  • Tetanus
  • metaldehyde
    • snail and slug baits
  • Pb
    • goes to bone
    • affects CNS and seizures
42
Q

Strychnine Tox

TX

A

Prevent asphyxiation

  • O2
  • Intubation

Control seizures: benzos, barbituates

Emesis

  • Do it
  • May not actually be effective tho

Activated charcoal

Ammonium chloride

  • ion trapping

If acidotic

  • bicarb

Forced diuresis

*aggressive aggressive treatment

43
Q

Salt Toxicity

(water deprivation/sodium ion toxicosis)

A

Water deprivation or consumption of large amount of salt

  • mechanical failure
  • frozen troughs

Most common in pigs, can be seen in cattle

Mechanism

  • diffusion of sodium into CSF when Na levels high

When plasma Na levels drop

  • Na leaves CSF slowly
  • attracts water to maintiain osmotic balance
    • inc CSF volume and pressure
44
Q

Salk toxicity

Clinical signs

A

Primarily CNS

  • salivation
  • inc thirst
  • abdominal pain
  • diarrhea

Signs progressive

  • circling
  • wobbling
  • aimless wandering
  • head pressing
  • blindness
  • seizures
  • partial paralysis

Cattle

  • May be belligerent and uncoordinated

Toxicity: 2.2 g/kgs swine, equine, bovine

45
Q

Salt Tox

DX

A

Na levels > 160 mez/L

  • esp if CSF levels > serum

Brain Na > 2000 ppm in swine and cattle

Differentiate from

  • polio
  • lead
  • pesticides
  • encephalitis
46
Q

Salt Tox

TX

A

Slow rehydration

  • over 2-3 days
  • serum sodium levels should be lowered at 0.5-1.0 mEz/l/hour
  • IV hyperosmotic fluids low in Na
  • Furosemide
    • ​sodium/K transporters, will dec Na uptake
    • loop diuretic
    • prevents pulmonary edema during fluid therapy
47
Q

Pharmaceuticals

A

Neuroactive

  • sleeping aids
  • antidepressants

Careless storage

Top culprits

  • vicodin (pain)
  • synthyroid (hypothyroid)
  • zocor and lipitor (high cholesterol)
  • Lisinopril (high blood pressure)

*toxicoses may resemble human toxicities

48
Q

Xanax

(Alprazolam)

A

Benzodiazepine (anti-anxiety medication and sleep aid)

One of top 10 human meds that ASPCA receives calls for

49
Q

Mechanism of Action and clinical signs

A

MONITOR BP

Act at limbic, thalamic, hypothalamic level of CNS

Clinical signs (appear w’in 30 min of ingestion)

  • ataxia
  • depression
  • vomiting
  • tremors
  • tachycardia
  • diarrhea
  • ptyalism
  • low body temp

Some animals may initially show CNS excitation

50
Q

Diagnosis of pharm tox

A

Diagnosis

  • based on suspected ingestion and clnical signs
51
Q

Pharmaceutical tox

TX

A

Induce emesis with apomorphine if ingestion recent and no signs

Use gastric lavage with activated charcoal if toxic dose

Flumazenil

  • benzo antagonist
  • may be used for severe CNS depression

Addition

  • fluids
  • medications
  • support resp functions
52
Q

Zolpidem

(Ambien)

A

Sleep aids that act similar to benzos

  • non-benzo hypnotic drug

one of top 10 meds that ASPCA gets calls for

53
Q

Ambien

MOA

A

Inhibits neuronal excitation by binding to benzodiazepine omega-1 receptors

Rapid absorption from GI tract, highly bioavailable, signs usually resolve in 12 hours

Main clinical manifestations

  • ataxia
  • vomiting
  • lethargy
  • disorientation
  • hyper-salivation
  • hyperactivity/panting

*more for dogs

54
Q

Diagnosnis and TX for pharm tox

A

Based on suspected ingestion and clinical signs

Treatment: supportive and symptomatic

Toxicology (10 decks)

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