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Flashcards in Macrocyclic Lactones Deck (69):
1

Macrocyclic lactone drugs are important in what speices?

Livestock
*Have improved food production

2

Macrocyclic lactone
Drug history:

Awarded the 2015 Nobel prize for the discovery and development of these drugs (ivermectin specifically)

3

********Macrocyclic lactone
Are what type of drugs?

Endectocides
-Cidal and very long acting!
******-Have activity against BOTH nematodes (roundworms) and ectoparasites.

4

Macrocyclic lactone
Purified from

Streptomyces spp.

5

Macrocyclic lactone
Related drug groups?

Avermectins and mibemycins
*Spinosyn A (larger than 7 member ring*

6

What are the macrocyclic lactones?

Avermectin (ivermectin)
Milbemycin (moxidectin)

7

******What are the avermectins for use in food animals?

Ivermectin
Eprinomectin *OTC
Doramectin

8

******What are the milbemycins for use in food animals?

Moxidectin

9

******What are the spinosyns for use in food animals?

NONE

10

******What are the avermectins for use in small animals?

Selamectin (revolution)
Ivermectin (heartguard)

11

******What are the mibemycins for use in small animals?

Moxidectin (DOGS ONLY, proheart 6)
Mibemycin oxime (interceptor)

12

******What are the spinosyns for use in small animals?

Spinosyn A/D (comfortis)

13

******What are the avermectins for use in horses?

Ivermectin

14

******What are the mibemycins for use in horses?

Moxidectin

15

******What are the spinosyns for use in horses?

NONE

16

Macrocyclic lactone use in ruminants:

Labeled uses.
Formulations are specific to species.
There is significant overlap in antiparasitacide action between MLs in ruminants.
Topicals are more effective against biting lice.
Not indicated/labeled for but effective against horn flies... haematobia irritans, ivermectin and eprinomection, up to 4 weeks depending on the formulation!

17

******Macrocyclic lactone use in pigs:

*Labeled use
******Ivermectin: GI roundworms, lungworms, lice, and sarcoptic manage.
Doramectin: as indicated by the manufacturer

18

Macrocyclic lactone use in horses

*Labeled use
Ivermectin and moxidectin for GI roundworms.
-Ivermectin is better against G. intestinalis (bots)
-Modidectin is better against cyanthostomum (small stronglies)

19

Dogs
Ivermectin use:

Dirofilaira immitis PREVENTION; all macrocyclic lactones are effective against stage 3 and 4 larvae regardless of speices!
-Extra-label use: demodicosis, cheyletiella (zoonotic) and sarcoptes scabei (self-limiting zoonosis), otodectes ect.

20

Dogs
macrocyclic lactone*
Selamectin use:

Dirofilaria immitis (prevention), fleas (c. felis), otodectes spp, sarcoptes scabei, d. variablis

21

Dogs
macrocyclic lactone*
Mibenmycin oxime

Dirofilaira immitis prevention, GI roundworms, hookworms (zoonotic) and whipworms.

22

Dogs
Moxidectin use:
macrocyclic lactone*

Dirofilaria immitis (prevention) and hookworms only

23

******Dogs
macrocyclic lactone*
Spinosad (Spinosyn A/D) use

Fleas (dosing is lower in cats)

24

Cats
macrocyclic lactone*
Ivermectin use:

Dirofilaria immitis (prevention)

25

Cats
macrocyclic lactone*
Selamectin use:

Dirofilaria immitis (prevention), fleas (c. felis), otodectes spp., T. cati and A. tubaeforme (hookworm)

26

Cats
macrocyclic lactone*
Mibemycin oxime use:

Dirofilaria immitis (prevention), GI roundworms and hookworms.

27

******Cats
macrocyclic lactone*
Spinosad (spinosyn A/D):

Fleas

28

Severity scale of heartworm disease:
Class I:

Asymptomatic
+ antigen test
Need 30 worms for a positive HR test.

29

Severity scale of heartworm disease:
Class II:

Moderate pulmonary damage.
Coughing an Exercise Intolerance.

30

Severity scale of heartworm disease:
Class III:

Right CHF
Syncope
Anemia
Cachexia
Cor pulmonale

31

Severity scale of heartworm disease:
Class IV:

Caval syndrome plus..
Right CHF
Syncope
Anemia
Cachexia
Cor pulmonale
AND; Shock, DIC, jugular distention and mitral regurgitation.

32

How is the lifecycle of heartworm different in cats vs dogs?

Cats immune system will kill.
*Cats adult heartworms live 2-4 years, microfilariae rarely circulate. Seen 7-8 months after infection.

33

Heartworm disease life-cycle in the dog:

Mosquito ingests microfilariae, L1>L2>L3 10-14 days) *mosquito phase > Infective larvae aquire a new host > L4 (45-65 days in the tissue > Developing adult in the bloodstream (4-5 months)..
6-7 months post infection the mature adult appears in the bloodstream.
Adult heartworms live for 5-7 years in the blood.
Microfilariae can live 1-2 years.

34

What is the D. immitis treatment gap?

Shows periods of susceptibility to macrocyclic lactones and melarsomine. The treatment gap is the dotted line that represents when D immitis is not considered to be susceptible to macrocyclic lactones or melarsomine.

35

******Macrocyclic lactones treating D. immitis are effective during what phases?

0 to 30 days
L3 to midway L4.
*No effect to adult phase

36

******Melarsomine is effective in treating what phase of heartworm disease?

Adult females, antigen positive
Day ~120<
*No effect to larvae stage.

37

******Melarsomine (immiticide)
Use?

Arsenical compound
Only approved adulticide treatment for heartworm.
Labeled for IM administration in 2, 3, or 4 applications.
Treatment for 4-6 months!!!
Kills rapidly.

38

******Melarsomine (immiticide)
RISKS?

Kills rapidly increases risks for..
-Pulmonary thromboembolic events
-Risks hypersensitivity reactions
-AVOIDING these possible side-effects is the ENTIRE point of HW treatment strategy***
-Really toxic in cats!!
******GIVE WITH CORTICOSTERIODS******

39

****Melarsomine (immiticide) is contraindicated in...

ABSOLUTELY CONTRAINDICATED IN DOGS WITH CAVAL SYNDROME

40

******What is Wolbachia?

Obligate, intracellular, gram negative bacteria/rickettsia.
Associated with survival of the filarial, production of the filarial (L3) and pulmonary and renal inflammation (via WSP surface protein)

41

******Wolbachia is sensitive to what drug?

Doxycycline sensitive.
-Current recommendation is to threat with doxycycline for 30 days prior to use of melarsomine. It reduces the worm burden prior to the adulticide (CRITICAL).
-Treatment with doxycycline alone holds promise as a sole adulticide in dogs for which melarsomine is contraindicated.

42

Current recommendation is to treat with THIS drug for 30 days prior to use of melarsomine. It reduces the worm burden prior to the adulticide (CRITICAL).

Doxycycline

43

******What is the second choice for treatment of dogs with heartworm disease with caval syndrome?

Doxycycline

44

******What is the split dose strategy?

3 applications.
After diagnosing a patient with heartworm disease...
Start on avermectin monthly, doxycycline 4 weeks, reduce activity..
After 4 weeks, administer the first melarsomine dose.
-Cage rest for 1 month, +/- steroids.
Wait one month then administer 2nd melarsomine dose, 3rd dose 24 hours later.
-Cage rest for one month. +/- steroids.
Animal requires testing every 3-6 months for the rest of its life.
*Reduction of activity so they do not throw a clot.

45

******Macrocyclic lactones
Pharmacodynamics:
#1 Noncompetitive agonist of glutamate-activated, chloride channel (Glu-Cl)

Noncompetitive agonist of glutamate-activated, chloride channel (Glu-Cl)
-Present in nematodes and arthropods, but not mammals.
-Induces FLACCID paralysis of somatic musculature and pharyngeal pumps.
-Inhibition of reproductive tract in female nematodes.

46

******Macrocyclic lactones
Pharmacodynamics:
#2 Agonist of GABA receptors:

Found in the ventral nerve cord and head of nematodes.
Requires much higher drug concentrations than for Glu-Cl inhibition.
Effects on mammalian GABA receptors may be the cause of toxic effects of MLs.

47

Macrocyclic lactones
Administration:

Formulations available in doses ranging from 3 ug/kg (dogs) up to 500.
Some release drug for up to 135 days.
Some provide alternating release of Ivermectin and Albendazole for up to 100 days.
Administered: SC, IM, PO, topical (pour-on)/PO_

48

Macrocyclic lactones
Bioavailability:

Highly variable***
Highly lipophilic drugs are pootly absorbed in the ruminant GI tract.
Selamectin BA topical: 5% in dogs and 75% in cats.
Ivermectin BA oral: 95% in dogs and 25-33% in cattle.

49

******Distribution of Macrocyclic lactones:

Benefits of Macrocyclic Lactones... *help keep the drug in the system longer.
Rapidly distributes to adipose tissue, serves as a depot,
Slow elimination.
Slow metabolism
Undergoes enterophepatic recycling
-----------------------

Extensively distributed to the lung and skin.
Permeates the BBB.

50

Macrocyclic lactones
Metabolism:

5-25% of administered dose is metabolized in the liver (sheep and cattle)

51

Macrocyclic lactones
Elimination:

~2 - 7 days
95% fecal and 5% urine (parent compound)
Enterophepatic recycling; 20% is secreted in the bile
******-Avermectins are eliminated in the milk!!!
Use is restricted to non-lactating animals;
Exceptions: Eprinomectin (topical) in cows an Moxidectin (topical) can be given to cows.******
P- glycoprotein is required to move Macrocyclic lactones drugs out of tissues.

52

Macrocyclic lactones require what to move the drug out of the tissue?

P- glycoprotein

53

******What is p-glycoprotein?

P-gp is an ATP dependent, broad specificity, cellular efflux pump.
-Cluster of differentiation 243 (CD 243)
-Gene: MDR1, ABCB1
Homologues are expressed in many organisms including parasites.
In mammals tissue expression includes; brain capillary endothelium, small intestinal epithelium, biliary canalicular cells, renal proximal tubular cells, placenta and testes.

54

MDR1 mutations

4 nucleotide frame deletion (mutation)
P-gp restricts drug penetration into the brain.
*Mutation seen in collies.

55

What is the mutation observed in collies?

Have a 4bp, inactivating deletion (ABCB1-1^)
Homozygotes do not have a functional P-gp
Ivermectin levels in brans of ABCB1 (-/-): White mice 87:1
Increase (ivermectin)brain may activate mammalian GABA receptors.

56

******Dog breeds associated with g-gp gene mutations:

Increase MBR1 (-/-)
Border collies*
Longhaired Whippet*
Min. Australian Shepherd*
Australian Shepherd*
Waller*
White Swiss Shepherd*
Silken Windhound*
Old English sheepdogs*
Shetland Sheepdogs*
Border Collie*
English Shepherd*
German Shepherd*
McNab*
*White feet don't treat*
*Breeding increases the mutation- breeders need to treat!!

57

******Adverse effects of toxicity of Macrocyclic lactones

Vomiting, tremors, ataxia, mydriasis, blindness and seizures.

58

******Dogs: wild type
-Ivermectin toxicity:

Dogs: wild type
-Ivermectin becomes toxic at more then 160x the normal dose.
Deaths occur at 6000x the normal dose (LD50-12,000x)

59

******ABCB1 -/-
Ivermectin becomes toxic at..

<2x the normal dose.
Signs begin at 4 hours of treatment.
-Safer alternate macrocyclic lactones
--Selamectin has no adverse effects in ABCB1 (-/-) collies at 6.x the normal dose.
--Mibemycin oxime does NOT cross the blood brain barrier.

60

******What are the alternative drug choices of ivermectin in dogs with ABCB1 (-/-)?

--Selamectin has no adverse effects in ABCB1 (-/-) collies at 6x the normal dose.
--Mibemycin oxime does NOT cross the blood brain barrier.

61

Combining this drug with macrocyclic lactones increases BBB permeability and toxicity..

SPINOSAD

62

macrocyclic lactones adverse effects in cats:

Signs start within 10 hours of overdose.
No signs noted in kittens at 4x normal cat dose
no signs in adult cats at 30x the normal cat dose

63

In ALL species with ANY of the macrocyclic lactones you will see

HYPERSENSITIVITY reactions in animals with large worm burdens.

64

Horses with macrocyclic lactones toxicity:

Signs start at 9-10x normal dose

65

Cattle macrocyclic lactones toxicity:

Start at ~12x normal dose (SC injection)

66

Pigs toxicity of macrocyclic lactones

Adults: signs start at 100x normal dose
Piglets: more sensitive.

67

******What are the mechanisms of resistance to macrocyclic lactones?

Currently uncommon, but on the increase.
******More resistant organisms have mutation or increased expression of P-gp.******
Ivermectin-resistant strains: Haemochus species in sheep and goat, trichstrongulus in cattle
treatment options:
-verapamil reverses p-gp and is being tested as an additive
-moxidectin currently retains activity.
Lower-responder strains of D. immitis are being reported in SE US.

68

What are the Avermectin drugs?

Ivermectin
Selemectin
Eprinomectin
Doramectin

69

What are Milbemycin drugs?

Moxidectin and Mibemycin oxime.