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
Describe the MOT of Antidepressant toxicity, specifically TCAs.
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
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
Chewing Disease
Locoweeds
* Astragalus
* Oxytropis
* Swainsona
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
