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Pharmacology II > LEC 25 - Macrocyclic Lactones > Flashcards

LEC 25 - Macrocyclic Lactones Flashcards

1
Q

What do macrocylic lactones work against?

A

Nematodes and ectoparasites

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2
Q

What are macrocyclic lactones made from?

A

Streptomyces spp.

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3
Q

What are the two major groups of macrocyclic lactones?

A

Avermectins and milbemycins

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4
Q

What avermectins are used in food animal?

A

Ivermectin, eprinomectin, and doramectin

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5
Q

What avermectins are used in small animals?

A

Selamectin and ivermectin

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6
Q

What avermectins are used in horses?

A

ivermectin

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7
Q

What mibemycins are used in food animal?

A

Moxidectin

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8
Q

What mibemycins are used in small animals?

A

Moxidectin and milbemycin oxime

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9
Q

What mibemycins are used in horses?

A

Moxidectin

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10
Q

How do macrocyclic lactones work?

A

Activate two ligand-gated, chloride channels. Glutamate-activated, chloride channel. GABA receptor.

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11
Q

What happens when macrocyclic lactones activate glutamate-activated chloride channels?

A

Hyperpolarizing. Flaccid paralysis of somatic musculature and pharyngeal pump. Inhibition of reproductive tract in female nematodes.

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12
Q

Is the action of macrocyclic lactones reversible or non-reversible at the chloride channels?

A

non-reverisble

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13
Q

Where are GABA receptors found in nematodes?

A

Ventral nerve cord and head

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14
Q

What is the difference about ML’s effects on gaba receptors compared to chloride receptors?

A

Need high concentrations of the drug to effect GABA receptors therefore probably the reason for ML’s adverse effects.

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15
Q

How are ML’s adminstered?

A

SC, IM, PO, and topical(w/ secondary oral)

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16
Q

What is the absorption like in ruminants for ML’s?

A

Highly lipophilic drugs are poorly absorbed in ruminant GI tract.

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17
Q

How long do formulations of ML’s last?

A

135days

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18
Q

Where do ML’s distribute to?

A

Adipose tissue, serves as depot for the drug. Slows elimination as well. Will also go extensively to the lung and skin. Can get past the BBB.

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19
Q

How are ML’s metabolized?

A

Oxidation in the liver.

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20
Q

How are ML’s eliminated?

A

95% fecal and 5% urine (as parent compound)

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21
Q

What is the process of enterohepatic recycling that occurs with ML’s?

A

20% of metabolites, parent compounds. Leads to prolonged effects of the drug

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22
Q

Where are avermectins eliminated from?

A

Milk, therefore use is restricted in non-lactating animals. The exceptions to this are eprinomectin and moxidectin.

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23
Q

What is P-gp?

A

ATP-dependent, broad specificity efflux pump

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24
Q

What another names does p-gp go by?

A

MDR1, ABCB1, or CD243

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25
Q

Where is p-gp expressed in the mammalian body?

A

Brain capillary endothelium, SI epithelium, biliary canalicular cells, renal proximal tubular cells, and placenta/testes

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26
Q

What three places of p-gp expression are important to ML’s excretion?

A

Brain, Small intestine, and biliary system

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27
Q

What mutation occurs in collies? What is it’s effects?

A

4bp, inactivating deletion. Homozygotes have a non-functional P-gp. Ivermectin levels in brain increase dramatically. Then lead to activation of GABA receptors.

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28
Q

What are the ten breeds of dogs that are most likely to have the MDR1 mutation?

A

Collie, longhaired whippet, shetland sheepdog, miniature australian shepherd, silken windhound, McNab, Australian shepherd, Waller, White swiss shepherd, and old english sheepdog.

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29
Q

What are the signs of toxic effects of ML’s?

A

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

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30
Q

When do OD signs from ML’s appear in cats?

A

10 hours from time of ingestion. But safe at 30x’s the normal cat dose. For kittens it is 4x’s the cat dose.

31
Q

How much ML does it take to see signs of toxicity in horses?

A

9 to 10x’s the dose

32
Q

How much ML does it take to see signs of toxicity in cattle?

A

~12 x’s the dose

33
Q

How much ML does it take to see signs of toxicity in adult pigs?

A

100 x’s the dose

34
Q

When do you see hypersensitivity with ML adminstration?

A

With large worm burden

35
Q

How much ML does it take to see signs of toxicity in a wildtype dog?

A

160x’s the dose, death will occur at 6,000 x’s the dose

36
Q

How much ML does it take to see signs of toxicity in a ABCB1 mutant dog? How long does it take to see?

A
37
Q

What is a safe alternative with ML’s in collies?

A

Milbemycin oxime, because it does not cross the BBB. Selamectin would also work because it has a much higher toxic dose.

38
Q

What drug acts with ML’s to increase BBB permeability?

A

Spinosad

39
Q

What is ivermectin used for in dogs?

A

Dirofilaria (heartworm), sarcoptes scabiei, Otodectes, Demodicosis, Cheyletiella, Pneumonyssus (nasal mites)

40
Q

What is selamectin used for in dogs?

A

Heartworm, Fleas, Otodectes, Sarcoptes scabiei, Dermacentor variablilis

41
Q

What is milbemycin oxime used for in dogs?

A

Dirofilaria immits, GI roundworms, Hookworms, and whipworms

42
Q

What is moxidectin used for in dogs?

A

Heartworm and hookworms

43
Q

What three ML’s are used in cats?

A

Ivermectin, selamectin, and milbemycin oxime

44
Q

What is ivermectin used for in cats?

A

heartworm

45
Q

What is selamectin used for in cats?

A

heartworm, fleas, otodectes, T. cati, and A. tubaeformae

46
Q

What is milbemycin oxime used for in cats?

A

Heartworm, GI roundworms, and hookworms

47
Q

What is the lifecycle of a heartworm?

A

Mosquito ingests microfilariae. Goes from L1 to L3 in mosquito in about 2 weeks. Mosquito bites host and infects. L3 for 3 to 4 days. L4 for 45 to 65 days. L3 adn L4 are spent in the tissue. Then becomes a developing adult for 4 to 5 months. Then finally a mature adult producing microfilariae. Both of which are in the blood stream phase.

48
Q

How long do heartworm live in dogs?

A

Adults, 5 to 7 years. Microfilariae 1 to 2 years.

49
Q

How long do heartworm live in cats?

A

Adults, 2 to 4 years. MIcrofilariae rarely circulate.

50
Q

Class 1 Heartworm Infection -

A

Asymptomatic, (+) antigen test

51
Q

Class 2 Heartworm Infection -

A

Moderate Pulmonary Damage with coughing and excercise intolerance.

52
Q

Class 3 Heartworm Infection -

A

Right CHF, syncope, anemia, cachexia, and cor pulmonale

53
Q

Class 4 Heartworm Infection -

A

Class 3 along with shock, DIC, jugular distention, and mitral regurgitation

54
Q

What is Wolbachia?

A

Obligate, intracellular, gram (-), bacteria/rickettsia

55
Q

What is Wolbachia associated with?

A

Survival/production/infectivity of filaria along with pulmonary and renal inflammation due to WSP surface proteins

56
Q

What drug can kill Wolbachia?

A

Doxycycline

57
Q

What is the recommendation protocol for heartworm treatment in regards to Wolbachia?

A

Treat with doxycycline for 30 days prior to melarsomine. Reduces worm burden prior to adulticide.

58
Q

What is done if for whatever reason there is a contrindication for melarsomine use?

A

Use doxycylcine alone as sole adulticide in dogs

59
Q

What does it mean when you get a (+) heartworm test?

A

30+ adult female worms

60
Q

What is the DOC for heartworm treatment?

A

Melarsomine

61
Q

How is melarsomine adminstered?

A

IM

62
Q

What do you have to worry about when giving melarsomine?

A

Pulmonary thromboembolic events and hypersensitivity reactions

63
Q

What is melarsomine contraindicated in?

A

Dogs with Caval Syndrome

64
Q

Where does ivermectin work in the heartworm lifecycle?

A

L3/4, while the larvae is in the tissue phase

65
Q

What two ML’s are used in pigs?

A

Ivermectin and doramectin

66
Q

What is ivermectin used for in pigs?

A

GI roundworms, lungworms, lice, and sarcoptic mange

67
Q

What is doramectin used for in pigs?

A

as indicated

68
Q

What two ML’s can be used in horses?

A

Ivermectin and moxidectin

69
Q

What is ivermectin used for in horses?

A

Gastrophilus intestinalis

70
Q

What is moxidectin used for in horses?

A

Cyanthostomum sp.

71
Q

Where do you see invermectin resistance?

A

Haemochus in sheeps and goats. Trichostrongylus in cattle.

72
Q

What drug is being looked into as an additive to ML’s to combat resistnace? Why?

A

Verapamil, reverses P-gp

73
Q

What is thought to be the mechanism behind resistance to ML’s ?

A

Increased expression of P-gp

Pharmacology II (20 decks)

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