Lecture 14 - CNS III Flashcards
What can be seen below?
What makes these products so popular?
Pyrethrins and Pyrethroids
(Permethrin, phenothrin, cypermethrin, deltamethrin, Pyrethrin I & II, fluvalinate, tefluthrin etc)
25% of world’s insecticide market
They are popular b/c they are less toxic and do not persist in the envt as
compared to other insecticides (eg OC have been banned for the most part b/c they persist in the envt and OP are much more toxic then pyrethrins and
pyrethroids).
List the sources of Pyrethrins and Pyrethroids
– Pyrethrins are natural ______ produced by ______ (________ - Not the horticultural variety) flowers
– Pyrethroids are ________
– Found in numerous formulations including sprays, dusts, granules, aerosols, collars and shampoos
* ____-____% in ready-to-use products; ___% in concentrates for dilution
– ______ control products are the main source of poisoning in small animals; mainly used for controlling?
– Pyrethrins are natural insecticides produced by
pyrethrum (Chrysanthemums - Not the horticultural variety) flowers
– Pyrethroids are synthetic
– Found in numerous formulations including sprays,
dusts, granules, aerosols, collars and shampoos
* 0.05-0.2% in ready-to-use products; 2% in concentrates
for dilution
– Flea control products are the main source of poisoning in small animals
mainly used for controlling ticks, fleas , lice and mosquitos
Pyrethrins and Pyrethroids produce?
Rapid knockdown effects on insects
Type II pyrethroids have a ?
cyano group which enhances
insecticidal activity
Pyrethroids come as type I and type II depending on chemistry and potency.
type I (lacking a cyano group) and type 2 (with cyno group)
Potency is enhanced with the addition of a cyano group
Synergists function to?
List some examples.
Inhibit metabolism (CYP450 , e.g., piperonyl butoxide, sesamex, piperonyl
cyclonene, etc., are added to increase stability & effectiveness
In addition Synergists such as piperonyl butoxide, sesamex, piperonyl
cyclonene, etc are added to enhance insecticidal activity, increase stability and effectiveness.
This is accomplished by inhibiting mixed function oxidases, enzymes that
destroy pyrethrum; unfortunately, this also potentiates mammalian toxicity.
Describe the toxicity of Pyrethrins and Pyrethroids. List the susceptible species.
- Variable: depends on compound and animal
species - Susceptible species: cats, dogs and fish
– Cats are very sensitive and more likely than dogs to develop toxicosis - Due to low glucuronidation capacity
- Toxic doses are unknown in most cases
– Pyrethrin LD50 in dog = 260->600mg/kg
Describe the ADME of Pyrethrins and Pyrethroids.
* Absorption varies depending on ____ of exposure
– Up to 70% ___ and < 2% _____ absorption
* Low ____ toxicity due to rapid hydrolysis in GI tract
* ________ → rapid and wide distribution
* Metabolized in the ____ by oxidation, hydrolysis and conjugation with glucuronide, glycine, sulfate,
taurine or glutamate. OPs inhibit __________ –> ↑toxicity of pyrethroids
* Excreted in ____ and ____
- Absorption varies depending on route of exposure
– Up to 70% GI and < 2% dermal absorption - Low oral toxicity due to rapid hydrolysis in GI tract
- Lipophilic → rapid and wide distribution
- Metabolized in the liver by oxidation, hydrolysis
and conjugation with glucuronide, glycine, sulfate,
taurine or glutamate. OPs inhibit hydrolysis
↑toxicity of pyrethroids - Excreted in urine and feces
Cats are deficient in ?
UDP-glucuronosyltransferase deficiency in cats
Describe the MOT of Pyrethrins and Pyrethroids
– Slow down _______ and prolong ______ of voltage-sensitive Na+ channels
* Repetitive firing predominates in type ___pyrethroids; membrane depolarization predominates in type ___ pyrethroids
– Direct action on sensory nerve endings –> repetitive firing –> __________
– Inhibit voltage-gated ______ (maxi) channels
– High type II pyrethroid doses antagonize ______-gated chloride channels –> seizures
– Slow down closing and prolong opening of voltage-sensitive Na+ channels
* Repetitive firing predominates in type I pyrethroids; membrane depolarization predominates in type II pyrethroids
– Direct action on sensory nerve endings –> repetitive firing –> paresthesia (pins and needles)
– Inhibit voltage-gated chloride (maxi) channels
– High type II pyrethroid doses antagonize GABA-gated chloride channels –> seizures
Type II Pyrethroids delay ?
inactivation for long periods
Type I Pyrethroids prolong?
Prolong opening for short periods
List the clinical signs of Pyrethroid and Pyrethrin toxicity.
- Convulsions, muscle tremors, paresthesia, ataxia, depression or hyperexcitability
- Cats exhibit ear twitching, paw shaking, shivering and mydriasis
- Anorexia, diarrhea, vomiting, and increased salivation are observed
- Bradycardia, dyspnea, hyperthermia and sudden
death from respiratory failure - Cats are more likely than dogs to be poisoned
How do you Dx Pyrethroid and Pyrethrin toxicity?
- History of exposure or use
- Clinical signs and rule out other insecticides
- Analysis of pyrethrin/pyrethroid residues on skin
What are the DDx for Pyrethroid and Pyrethrin toxicity?
- Strychnine, metaldehyde, OPs and CMs,
tremorgenic mycotoxicosis, methylxanthines,
fluoroacetate
How do you distinguish between OPs and CMs?
Distinguish using atropine
test and ChE activity
How do you treat Pyrethrin and Pyrethroid toxicity?
- Decontamination: Topical exposure
– Bathe patient thoroughly with water and mild
hand dishwashing detergent. Large animals may
require a garden hose and a scrub in addition to
detergent - Decontamination: Oral exposure
– Emesis (within 1-2 h), contraindicated if product
contains petroleum distillates
– Activated charcoal is not routinely
recommended but can be used if a spot-on
product was ingested by a cat - IV lipid emulsion can be tried
- Symptomatic Tx
– Diazepam or phenobarbital for seizures
– Methocarbamol for severe muscle tremors/seizures
– Atropine should be avoided (CNS stimulation) - Supportive Tx
– IV fluids
– Monitor and correct blood glucose with IV dextrose
– Thermoregulation: hyperthermia from excess
muscle activity can rapidly become hypothermia
during treatment (following bathing and sedation)
Hypothermia enhances nervous activity by ___________ ____ channel kinetics
slowing Na+-
What toxin is pictured below?
What is its function?
Bromethalin
For anticoagulant rodenticide-resistant mice & rats
List the sources of Bromethalin.
Sources
– Rodenticide (Hot Shot, Assault, Mouse Killer,
Vengeance, Trounce, etc). [‘Place packs’]
List the susceptible species of Bromethalin toxicity.
Susceptible species: dogs, cats, rabbits. Cats
are highly sensitive
Describe the ADME of Bromethalin.
- ADME: ______ absorption from ____ tract (plasma levels peak in ___h), metabolized by _____ (?) in the liver to __________ (toxic metabolite)
- It is _______ and slowly eliminated via _____
- ADME: rapid absorption from GI tract (plasma levels peak in 4h), metabolized by mixed function oxidases (MFO) in the liver to desmethyl- bromethalin (toxic metabolite)
- It is lipophilic and slowly eliminated via bile
Describe the MOT of Bromethalin.
- Uncouples oxidative phosphorylation in CNS mitochondria—> decreased ATP production
– Diminishes Na+/K+-ATPase activity –> Na+ flows into cells down concentration gradient –> cerebral edema and high CSF pressure - Fluid filled vacuoles form in myelin sheaths and decrease nerve impulse conduction
- Induces membrane lipid peroxidation in brain
List the clinical signs of LOW dose Bromethalin toxicsosis.
– Tremors, depression, hind limb ataxia and paresis,
vomiting, vocalization (cats) and lateral
recumbency, anisocoria and behavioral changes
List the clinical signs of HIGH dose Bromethalin toxicsosis.
– Hyperexcitability, severe muscle tremors,
hyperthermia, running fits, circling, seizures,
nystagmus, CNS depression and death
– Schiff-Sherrington (rigid forelimbs & flaccid
paralysis of hind limbs) and decerebrate (hindlimb
extensor rigidity & forelimb flexion) postures
How do you Dx Bromethalin toxicosis?
- History of exposure and clinical signs
- Postmortem lesions (diffuse white matter
vacuolization in CNS) - Chemical analysis in fat, brain and other
tissues
List the DDx of Bromethalin toxicosis.
- Strychnine, fluoroacetate, metaldehyde,
salt poisoning, alcohol intoxication,
tremorgenic mycotoxicosis, tick paralysis
How do you treat Bromethalin toxicosis.
- Decontaminate
– Emesis if within 1 h post-exposure and in the
absence of clinical signs
– Gastric lavage within 2-4 h post-exposure
– Give repeated doses of activated charcoal
– Saline cathartic (avoid magnesium-containing
solutions to prevent CNS depression) - Control cerebral edema
– Give diuretics (furosemide and mannitol) and
methylprednisolone or dexamethasone - Administer diazepam or a barbiturate for
seizures - Administer crystalloid fluids to support
blood pressure and perfusion - Treat hyperthermia
- Provide supplemental feeding
– Maintain caloric intake because animals exhibit
prolonged anorexia during recovery - IV lipid emulsion was used to successfully
treat a Pit bull terrier
List the sources of Antidepressants.
– Tricyclic antidepressants (TCAs)
– Selective serotonin reuptake inhibitors (SSRIs)
– Monoamine oxidase inhibitors (MAOIs)
Is Antidepressant toxicity common in companion animals?
↑ use of antidepressant by humans →↑ animal exposure risk
Used to Tx behavioral problems in pets
How do companion animals get exposed to Antidepressants?
– Ingestion of human medicines, overdosing and
suicide attempts (‘take my pet with me’)
– Clomipramine used for separation anxiety in dogs
Which species are susceptible to Antidepressant toxicity?
Dogs and cats
Describe the MOT of Antidepressant toxicity, specifically TCAs.
List the clinical signs of Antidepressant toxicity.
- Ataxia, lethargy, behavioral changes (e.g.,
disorientation, anxiety, aggression),
hyperactivity and seizures followed by
depression to semi-comatose state - Hyperthermia or hypothermia, mydriasis,
ileus, vomiting, cardiac arrhythmias,
hypotension, shock and death - Note: TCAs have a narrow safety margin
How do you Dx Antidepressant toxicity?
- History of exposure
- Clinical signs
- Detection of TCAs in urine or serum
How do you Tx Antidepressant toxicity?
- Emergency! - prompt & aggressive Tx
1. Decontaminate
– Emesis for very recent exposures (<15 min) is
done under veterinary supervision. It is
preferable not to induce emesis
2. Administer activated charcoal and a cathartic
3. Gastric lavage for very large ingestions
4. Monitor animal for hypotension, hyperthermia
and arrhythmias and correct if necessary
5. Symptomatic and supportive Tx
– IV fluids for cardiovascular support/hypotension
– Do not use atropine for bradycardia if present - Atropine may potentiate anticholinergic effects
6. Give diazepam for seizures and if not successful
induce anesthesia with a barbiturate
7. Treat hyperthermia
– External cooling (immerse in or spray patient
with cool (not cold) water; wrap in cool wet
towels; fanning; evaporative cooling e.g., by
applying isopropyl alcohol on foot pads, pinna,
groin, and under the forelegs)
– Cool water enema
– Cool IV fluids
List the sources of Fumonisins.
Fumonisins
[equine leukoencephalomalacia (ELEM), blind staggers]
* Sources
– Mycotoxins produced by fungi of Fusarium spp.
in corn and corn-based foods
* Exist in at least three forms: Fumonisin B1, B2 and B3.
Fumonisin B1 is the dominant toxin
1934-5: 5000 horses died in IL
1901-2: 2000 horses died in US
List the predisposing factors of Fumonisin toxicsosis.
– Conditions that promote fungal growth and toxin
production: midsummer drought, early wet fall,
early frost and delayed harvests
Describe the ADME and susceptible species of Fumonisin toxicsosis.
- Absorbed from ____ tract with ___-__% systemic bioavailability
- Accumulate in (3?)
- Eliminated primarily via _____ with only
trace amounts in ____ and ____ - Susceptible species:?
- Absorbed from GI tract with 3-6% systemic bioavailability
- Accumulate in liver, kidney and intestine
- Eliminated primarily via feces with only
trace amounts in urine and bile - Susceptible species: livestock –
horses, ponies, donkeys and pigs
Describe the MOT of Fumonisin toxicosis.
- Inhibit sphinganine and sphingosine N-
acyltransferase (ceramide synthase) –> impaired sphingolipid synthesis –> accumulation of sphinganine and sphingosine with decrease sphingolipids
–> impaired cell to cell communication and
signaling - Loss of membrane structure: barrier function of
endothelial cells is disrupted –> edema and
hemorrhage - Inhibition of cardiac Ca++ channels in pigs –> Left-side heart failure & pulmonary edema
Disruption of sphingolipid metabolism
Fumonisins Inhibit __________ and _______
resulting in inhibition of sphingolipid synthesis.
This leads to the accumulation of ________ in tissues and blood, which is very _______ and decreases the production of ____ ________ sphingolipids → impaired cell to cell _______ and _____ structure
Inhibits sphingosine and sphinganine N-acyltransferases (ceramide synthase)
resulting in inhibition of sphingolipid synthesis.
This leads to the accumulation of sphinganine in tissues and blood.
Sphinganine is very cytotoxic and decreases the production of cell membrane
sphingolipids → impaired cell to cell communication and membrane structure
6
Describe the clinical signs of Fumenisin toxicosis in Horses.
- Horses: Neurotoxic syndrome
– Onset: 7-90 days; Course: short
– Mania to depression in 4-12h; death in 2-3 days
– Frenzy, anorexia, depression, ataxia, blindness,
holding head low, paralysis of lips and tongue
– Head pressing, stupor, hyperesthesia and
hyperexcitability, profuse sweating, delirium,
terminal convulsions and death. Permanent
damage in survivors
Describe the clinical signs of Fumenisin toxicosis in Swine.
- Porcine pulmonary edema (PPE)
– Caused by pulmonary hypertension with
transudation of fluids resulting in interstitial
pulmonary edema and hydrothorax
– Acute onset of dyspnea, cyanosis of mucous
membranes, weakness, recumbency, and death, often
within 24 h. Surviving pregnant sows may abort - Sublethal exposure: hepatotoxicosis with
reduced growth and icterus
How do you Dx Fumenisin toxicosis.
- History of exposure and clinical signs
- Analyze feed for fumonisins
How do you Tx Fumenisin toxicosis.
- There is no effective treatment
- Prevent toxicosis by avoiding moldy corn
– Difficult because corn may not be grossly moldy - Fumonisins exposure guidelines:
– Horses: <1ppm, ruminants: <30ppm, swine: <10ppm,
poultry: <50ppm, breeding ruminants & poultry: <15ppm
What toxin is pictured below?
Centaurea
(Yellow starthistle, Russian knapweed)
* Annual weed in western
US (CA, ID, OR, CO,
WA)
* Contains neurotoxins:
– Sesquiterpene lactones
(e.g., repin)
– Excitotoxins - aspartic
and glutamic acid
– DDMP
(2,3-dihydro-3,5-dihydroxy-6-methyl-4[H]-pyran-4-one)
Aggressive, no natural enemies, costly to eliminate
Describe the MOT of Centaurea toxicosis.
- Interaction with __________ transporter and selective death of _________ neurons esp. in substantia nigra and globus pallidus
- Similar to Parkinson’s disease
- Damage to neural areas supporting cranial nerves ?
- Susceptible species: _______
– Requires __________ (30-60 days) and _____ dietary intake but has an abrupt onset
- Interaction with dopamine transporter and selective death of dopaminergic neurons esp. in substantia nigra and globus pallidus
- Similar to Parkinson’s disease
- Damage to neural areas supporting cranial nerves V, VII, IX and XII
- Susceptible species: horses
– Requires prolonged (30-60 days) and large dietary intake but has an abrupt onset
Name the following nerves:
V
VII
IX
XII
Trigeminal
Facial
Glossopharyngeal
Hypoglossal
Which species are susceptible to
Which species are susceptible to Centaurea toxicosis?
horses
– Requires prolonged (30-60 days) and large
dietary intake but has an abrupt onset
List the clinical signs seen in Centaurea toxicosis.
(Nigropallidal Encephalomalacia, Chewing Disease)
* Typical complaint: animals that were normal the previous day now “cannot ___ or ______”
* Excessive tone of ____ and ___ muscles
* _________ , mouth is held ____ with tongue _________, chewing movements without ability to _____ and __________
* Head tossing, animal cannot drink and dunks _____ into water and tips head _____ to assist in swallowing
* Depression with periods of excitability
* ________ edema, dehydration and death by starvation
(Nigropallidal Encephalomalacia, Chewing Disease)
* Typical complaint: animals that were normal the
previous day now “cannot eat or drink”
* Excessive tone of facial and lip muscles
* Yawning, mouth is held open with tongue
protruding, chewing movements without ability to
chew and swallow
* Head tossing, animal cannot drink and dunks head
into water and tips head back to assist in swallowing
* Depression with periods of excitability
* Pitting edema, dehydration and death by starvation
Chewing Disease
How do you Dx Centaurea toxicosis?
- History of plant consumption
- Clinical signs
How do you Tx Centaurea toxicosis?
- No treatment strategies have been successful
- May maintain horses on IV fluids and
enteral feeding via gastric tube - Prognosis is grave: animals die of starvation
or are euthanized
What is the toxic principle of Locoweeds?
indolizidine alkaloid,
swainsonine
Locoweeds
* Astragalus
* Oxytropis
* Swainsona
What is the ADME of Locoweeds?
– Readily absorbed in GI tract and distributed to all
tissues
– Crosses placental barrier to affect the fetus
– Secreted unchanged in milk milk is toxic to
nursing animals
* Toxicosis follows chronic locoweed ingestion
What is the MOT of Locoweeds?
- Inhibition of Golgi mannosidase II
disruption of glycoprotein processing
– Dysfunctional cellular adhesion molecules, circulating
hormones and membrane receptors
– Accumulation of oligosaccharide-glycosylated proteins
What are the Clinical Signs of Locoism
How do you Dx Locoism?
- History and evidence of consumption of
locoweeds. Examine feces and rumen contents - Clinical signs
- Demonstrate swainsonine in serum and low
serum α-mannosidase activity
How do you treat Locoism?
- There is no proven effective Tx
- Remove animals from pasture with locoweeds
List the sources of lead?
- Lead-based products (paints, batteries, lubricants,
toys, sinkers, curtain weights, shots, bullets, etc.) - Forage growing in lead contaminated soil
Tetraethyl Lead in gasoline used to be a
major source of Pb but was discontinued
Which species are susceptible to Lead toxicosis?
- Cattle, dogs and waterfowl are commonly affected
- Lead poisoning in other species is limited by
reduced accessibility, more selective eating habits,
or lower susceptibility. Swine are resistant
What is the ADME of Lead toxicosis?
- The most common exposure route is oral
- Absorption depends on physical form and route
of exposure. Rate of absorption is: metallic Pb <
Pb salts < organic Pb - 90% of absorbed Pb is bound to RBC. Highest levels in bone, teeth, liver, brain and kidney. Pb crosses the BBB in the young. Greater absorption in the young
- Most of the ingested Pb is excreted via feces (before absorption) with some in urine and bile
Pb-containing objects may be retained in reticulum in cattle
What is the MOT of Lead?
- Inhibits thiol (–SH) containing enzymes
- Displaces Zn2+ and Fe2+ in some metallo-enzymes
- Lowers GABA concentration and inhibits N-methyl-D-aspartate (NMDA)
glutamate receptors in the CNS - Inhibits membrane associated ion pumps
- Competes with and mimics Ca++ ions
- Inhibits hemoglobin and RBC synthesis
– Inhibits delta-aminolevulinic acid dehydratase (δ-
ALAD) and ferrochelatase
What are the clinical signs of Lead toxicity in cattle?
Cattle (CNS signs): Blindness, circling, head
pressing, ataxia, *seizures, mydriasis, muscle
spasms, opisthotonus, aimless running,
compulsive pacing and *depression followed by
hyperesthesia and aggression
What are the GI signs associated with Lead toxicosis?
Vomiting, reduced ruminal motility,
salivation, colic, anorexia, rectal sphincter paresis,
tucked abdomen and bloat followed by diarrhea
What are the clinical signs of Lead toxicity in waterfowl?
Paracute death or chronic disease with
anorexia, emaciation, muscle atrophy, weakness,
dysphonia, depression, coma and death
What are the clinical signs of Lead toxicity in dogs/cats?
GI upset predominates. Anorexia,
colic, emesis, salivation, diarrhea/constipation.
Anxiety, hysterical barking, jaw champing,
ataxia, blindness, muscle spasms, opisthotonus,
convulsions and depression
What are the clinical signs of Lead toxicity in Horses?
Chronic poisoning with segmental
demyelination, lower lip paresis, recurrent
laryngeal nerve paralysis “roaring”
* Dysphagia, weight loss, depression, weakness, colic,
diarrhea and death
How would you Dx Lead toxicosis?
- Blood tests: Pb levels in whole blood (note: >90%
of the Pb is bound to RBC)
– >0.6 ppm is diagnostic in most species. 0.35-0.6
ppm with clinical signs is diagnostic - Urinary Pb levels: > 0.75 ppm is diagnostic. Can do
test before and after treating patient with Ca-EDTA
(Pb levels increase greatly [>10×] after Ca-EDTA) - RBC ALAD activity and urinary ALA levels
- Radiography to detect Pb objects in GI tract
- Postmortem: lesions and Pb levels in liver/kidney
How would you treat Lead toxicosis?
- Decontaminate
– Remove Pb-containing foreign bodies from GI
tract via rumenotomy, gastrotomy or endoscopy
– Emesis, gastric lavage, cathartic, enema or
whole bowel irrigation - Chelation therapy
– Chelators bind Pb into a soluble form that is
excreted in urine
– Chelation agents: Ca-EDTA, D-Penicillamine
(Cuprimine), succimer (DMSA, Chemet),
dimercaprol (BAL: British anti-Lewisite)
How would you provide supportive and symptomatic treatment for lead toxicosis?
– Diazepam or barbiturates for seizures
– Treat cerebral edema with mannitol and
furosemide
– Maintain adequate hydration and nutrition
– Administer thiamine (aids in resolving CNS
signs)
