Toxicology Lecture 12 Ivermectin, Milbemycin, Moxidectin

Front 1

**Why can't you apply ivermectin to animals under 6 weeks of age?

Back 1

Blood brain barrier isn't fully formed, *kittens and calves

Front 2

*Avermectin is family of chemically related __________ produced within the mycelia of Streptomyces avermitilis.

Back 2

Macrocyclic lactones

Front 3

*What avermectin is used in some ant poisons?

Back 3

Abamectin

Front 4

What is the relative safety of ivermectin? Why?

Back 4

Relatively safe antihelminthic- rarely cross BBB

Front 5

True or false. Ivermectin will cross into milk.

Back 5

True

Front 6

***What specie is Ivermectin contraindicated in?

Back 6

Cholenians (turtles, tortoises)

Front 7

Why can't you use Ivermectin on collies?

Back 7

More susceptible to toxicosis because may carry a gene mutant and lack P-GLYCOPROTEIN (normally pumps things out of CNS)

Front 8

*what is the half life of ivermectin?

Back 8

LONG PLASMA HALF LIFE

Front 9

**Ivermectin toxicosis is most commonly reported in what 2 animal?

Back 9

Kittens (treating ear mites)
Dogs

Front 10

**What is the toxic/ lethal dose (LD50) of ivermectin in collies?

Back 10

LD50 is 0.15 to 0.2 mg/kg

Front 11

Is milbemycin or ivermectin a safer drug?

Back 11

Milbemycin

Front 12

What are the clinical signs of milbemycin toxicosis in collies? At what doses?

Back 12

Hypersalivation, ataxia, mydriasis & depression at 5 mg/kg; at 10 mg/kg all collies affected

Front 13

At what does of moxidectin do collies show clinical signs?

Back 13

After 0.09 mg/kg
-other dogs no signs at 0.9 mg/kg (>300 x pharm dose)

Front 14

What avermectin is safe to use on collies?

Back 14

Selamectin (revolution)
-Safe at 5x the recommended dose in collies

Front 15

*How do you determine if an animal is sensitive to ivermectin?

Back 15

A test is now available for drug sensitivity

Front 16

**What genes are responsible for the ivermectin sensitivity in collies?

Back 16

Was known as MDR1 (multidrug resistance) and is now called the ABCB-1delta gene

Front 17

What does the ABCB-1delta gene (previously known as MDR1) code for?

Back 17

P-glycoprotein
-protein complex that acts to pump medications out of the brain and back into blood stream
-without this increased penetration of macrocyclic lactones into the CNS

Front 18

**What is the mechanism of action of ivermectin Toxicosis? (4)

Back 18

1) Stimulates the presynaptic release of GABA
2) Enhances GABA's binding to postsynaptic receptors
3) May have a *direct GABA-like agonist effect
4) Interferes w/ glutamate-gated Cl channels

Front 19

*What does GABA do in mammalian systems?

Back 19

Is an inhibitor neurotransmitter at both pre- and postsynaptic neurons in the CNS
-opens chloride channels, thus allowing a Cl ion influx, which inhibits neural transmission by causing hyperpolarization of nerve cell membrane

Front 20

What is the mechanism of action of ivermectin toxicosis in the nervous system? Clinical signs?

Back 20

Binds to GABA-gated channels--> hyperpolarization and subsequent inhibition of neuronal depolarization ---> ataxia, weakness, disorientation, head pressing (cats), tremors, seizures, coma--> death

Front 21

What 5 systems does ivermectin toxicosis affect?

Back 21

1) Nervous system
2) Eye
3) GI
4) Respiratory
5) Cardiovascular

Front 22

What are the effects of ivermectin toxicosis on the eye?

Back 22

Mydriasis, central blindness & retinal edema

Front 23

What are the GI signs of Ivermectin toxicosis?

Back 23

Hypersalivation, vomiting, anorexia, diarrhea

Front 24

What are the respiratory effects of ivermectin toxicosis?

Back 24

Hypoventilation

Front 25

What are the cardiovascular effects of ivermectin toxicosis?

Back 25

If animal + heartworm and microfilaria then sudden death from anaphylactic shock

Front 26

Why are many patients euthanized due to ivermectin toxicosis?

Back 26

Due to long treatment
-severity of signs may not correlate w/ their persistence
-long half life

Front 27

What are 3 ways to diagnose ivermectin toxicosis?

Back 27

1) Potential exposure- worming history within last 2-3 days
2) Appropriate clinical signs **CNS depression
3) Chemical analysis
**Fat, liver, bile// kidney, serum **brain

Front 28

What is the treatment for ivermectin toxicosis?

Back 28

**No antidote
*Decontaminate: **repeated doses of activated charcoal may be needed bc of enterohepatic circulation

Front 29

***What do you want to avoid when treating ivermectin toxicosis?

Back 29

Avoid benzodiazepines (valium)
-may potentiate GABA binding and lead to prolonged recovery

Front 30

**Why is it really difficult to assess if an animal with ivermectin toxicosis is getting better with treatment?

Back 30

DIFFICULT TO PREDICT- does not appear to correlate with severity of signs

Front 31

*What is the major cause of death from ivermectin toxicosis?

Back 31

Checkbook fatigue

Front 32

**What are 2 treatments you should not use for ivermectin toxicosis?

Back 32

1) Physostigmine- was used in dogs
-doesn't effect clinical course of disease, causes SLUD
2) Picrotoxin- GABA antagonist
-was used in dogs, causes seizures

Front 33

Where are UMNs located in the body?

Back 33

In the brain

Front 34

Where are LMNs located in the body?

Back 34

In the ventral horn of the spinal cord and in the brain for CNS w/ motor function
-CN 3,4,5,6,7,9,10,11,12= all except 1,28

Front 35

If you pinch a dog's P3 with hemostats and doesn't respond what kind of lesion does the animal have?

Back 35

LMN lesion

Front 36

A dog has a weak jaw tone and a change in voice, what's the most likely cause?

Back 36

LMN lesion

Front 37

UMN lesion or LMN lesion..... normal to increased reflexes

Back 37

UMN lesion

Front 38

UMN lesion or LMN lesion..... decreased or absent reflexes

Back 38

LMN lesion

Front 39

*True or false. Muscle tone is a reflex.

Back 39

TRUE

Front 40

***What are the keys to diffuse LMN disease?

Back 40

Flaccid muscle tone & depressed or absent of reflexes in all 4 limbs!!!

Front 41

*What are the two primary signs of diffuse LMN disease?

Back 41

1) Decreased or absent reflexes
2) Decreased muscle tone

Front 42

**What are 3 common diffuse LMN diseases?

Back 42

1) Coonhound paralysis or polyradiculoneuritis
2) Tick paralysis
3) Botulism

Front 43

What are 3 less common diffuse LMn diseases?

Back 43

1) Polyneuritis
2) Myasthenia gravis
3 Black widow spider toxin

Front 44

What are 4 diagnostic tests for distinguishing different diffuse LMN diseases?

Back 44

1) Examine for ticks; dip in high exposure areas i.e. SE USA
2) ?Botulism toxin in feed or feces
3) EMG (+ for fibs and + sharps > 5 days) w/ coonhound paralysis
4) Nerve conduction velocity --> normal to decreased

Front 45

What is the toxin that causes tick paralysis?

Back 45

Essentially unknown, something in the saliva

Front 46

What is the distribution of tick paralysis?

Back 46

Regional distribution

Front 47

True or false. There really is a "tick season".

Back 47

Yes, it's a shared disease among dogs, cats, horses, cows, snakes, humans

Front 48

What is the mode of action of tick paralysis?

Back 48

-Neurotoxin interferes w/ calcium function in the release of Ach from the axonal terminal
-This inhibits depolarizaiton of LMNs w/ associated slowed synaptic transmission and reduced nerve conduction velocity

Front 49

*How do you diagnose tick paralysis?

Back 49

No specific test, ***diagnosis based on clinical signs and 24 hours response to DIPPING

Front 50

*What is the treatment for tick paralysis?

Back 50

Remove the tick!!!

Front 51

*After removing a tick how long should it take for the clinical signs of tick paralysis to resolve?

Back 51

Normally resolve in 24-48 hours after removal of the tick

Front 52

*What is the prognosis of tick paralysis?

Back 52

Good if tick is removed

Front 53

**What are the 2 primary signs of coonhound paralysis that differentiates it from tick paralysis?

Back 53

1) EMG abnormalities
***NO EMG abnormalities w/ tick paralysis
2) NCV reduced < 40 m/s
-normal to slightly decreased in tick paralysis.

Front 54

True or false. Tick paralysis causes EMG abnormalities.

Back 54

False, coonhound paralysis does

Front 55

How quick do nerves regenerate?

Back 55

1 mm/day or 1 in/month

Front 56

What is the EMG and NCV of botulism?

Back 56

Both are normal

Front 57

*How do you diagnose botulism?

Back 57

Multiple cases, bad food
-toxin in feed or feces

Front 58

*How long does it take botulism patients to recover in most cases?

Back 58

2-3 weeks

Front 59

*What is the treatment for botulism?

Back 59

Supportive care

Front 60

*When can you perform an EMG when trying to diagnose a LMN disease?

Back 60

After 5 days

Front 61

If simple demyelination, how long does it take a LMN disease to recover?

Back 61

2-3 weeks

Front 62

*How long does an animal have to for a nerve to regenerate to the muscle before it cannot regenerate?

Back 62

One year, or the muscle is permanently lost

Front 63

*What are the clinical signs of botulism toxin in small animals?

Back 63

Acute symmetrical quadriparesis w/ diffuse LMN dysfunction

Front 64

**What type of botulism toxin is most common in dogs?

Back 64

Type C