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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
Fumonisin MOA
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
Two diseases linked to fumonsins
ELEM (equine leucoencephalomalacia) PPE (porcine pulmonary edema)
27
Porcine pulmonary edema
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
Diagnosis of PPE
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
ELEM | (equine leukoencephalomalacia)
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
ELEM DX
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
Fumonisin tox TX
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
Tremorgenic mycotoxins
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
Ammoniated feed toxicosis
NPN (non-protein nitrogen sources) * urea * ammonium salts Found in high conc in some mineral licks affected species * bovine * caprine * ovide Bovine bonkers
34
Clinical signs of ammonia tox/imidazoles
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
Ammonia Toxicosis DX
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
Imidazole tox TX
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
NPN overdose tox TX
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
Strychnine
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
Strychnine MOA
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
Strychnine tox Clinical signs
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
Strychnine Tox DX
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
Strychnine Tox TX
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
Salt Toxicity (water deprivation/sodium ion toxicosis)
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
Salk toxicity Clinical signs
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
Salt Tox DX
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
Salt Tox TX
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
Pharmaceuticals
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
Xanax | (Alprazolam)
Benzodiazepine (anti-anxiety medication and sleep aid) One of top 10 human meds that ASPCA receives calls for
49
Mechanism of Action and clinical signs
**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
Diagnosis of pharm tox
Diagnosis * based on suspected ingestion and clnical signs
51
Pharmaceutical tox TX
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
Zolpidem | (Ambien)
Sleep aids that act similar to benzos * non-benzo hypnotic drug one of top 10 meds that ASPCA gets calls for
53
Ambien MOA
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
Diagnosnis and TX for pharm tox
Based on suspected ingestion and clinical signs Treatment: supportive and symptomatic

Toxicology (10 decks)

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