Macrocyclic Lactones

what are the 2 main classes of macrocyclic lactones

- avermectins: abamectin, ivermectin, doramectin, eprinomectin, and selamectin

- milbemycins: Nemadectin, moxidectin, and milemycin oxime

which drug class is considered the most widely used and broad-spectrum antiparasitic drugs in vet medicine

macrocyclic lactones

what gives rise to the embracing name endectocides by which MLs are classified

Unique combination of killing of endo and ectoparasites

what spp are doramectin and eprinomectin used for

livestock; eprinomectin is a semisynthetic avermectin developed for topical use in cattle

what is selamectin

- brand name revolution

- used in SA for fleas and heartworms

- Semisynthetic monosaccharide oxime derivative of doramectin more recently introduced into the market for control in dogs/cats

Minor chemical changes may have a ______ impact on the activity of the avermectin analogs

profound

What is the MOA of avermectins and Milbemycins

- selective toxic effects on insects, acarines, and nematodes but not cestodes and trematodes

- Paralytic effects are mediated through GABA and/or glutamate-gated chloride channels, collectively known as ligand-gated chloride channels

- Flaccid paralysis of the invertebrate somatic muscles is main MOA

ML endectocides cause paralysis and death of both arthropod and nematode parasites due to what

their paralytic effects on the pharyngeal pump, which affects nutrient digestion, and on the parasite somatic musculature limiting its ability to remain at the site of predilection in the host

why is moxidectin the preferred heartworm preventative over ivermectin

PD differences that allow for a difference in the interactions of moxidectin with the target parasite receptors that increase their pharmacological potency

Clinical efficacy of MLs is closely related to what aspect of the PK behavior

time of exposure of parasite to active drug, which is required to obtain optimal and persistent antiparasitic activity

Ivermectin, doramectin, and moxidectin are all at _______ concentrations in tissues compared to plasma

higher

Persistence of activity of MLs against adult and immature GI parasites is facilitated by what

their advantageous pattern of distribution and prolonged residence in digestive mucosal tissue

what is the most lipophilic endectocide agent

moxidectin

what accounts for larger distribution for moxidectin compared to other antiparasitic drugs

distribution to adipose: may act as a reservoir that contributes to long persistence of this molecule in blood and in different tissues of parasite location

what invalidates the use of ivermectin, moxidectin, and doramectin in dairy animals

a considerable excretion of these drugs occurs via mammary glands; topical moxidectin is approved for use in dairy cattle in some countries without a milk WD time

what is the result of efforts to identify MLs for use in dairy cattle

an avermectin-derivative, eprinomectin, has been developed for topical administration → substantially reduced distribution to milk compared to other MLs

list some PK features that contribute to extended broad spectrum persistence of MLs in ruminants

- Depot at administration site: absorption dependent elimination

- Strong adsorption to GI particulate digesta

- Extensive and reversible plasma-tissue exchange

- Fat reservoir

- Low rate of metabolism

- Extensive biliary and P-GP-mediated intestinal secretion

- Entero-hepatic recycling (minor)

- Slow deposition kinetics → sustained presence in target tissues → extended antiparasitic persistence

Moxidectin is advantageous in that its efficacy/persistence patterns work against __________-resistant nematode parasites

ivermectin

ML endectocides are highly effective in eliminating mites and suckling lice spp after which administration forms

SC and topical

what is ML lack of efficacy against trematodes and cestodes due to

deficiency of ML-specific binding sites in these parasites

True or false MLs possess ovicidal activity similarly to BZDs

false: they do not

what are the formulations of MLs for cattle

PO or topical formulations

what is the spectrum of MLs for ruminants

- Highly effective against immature and adult stages of different GI nematode spp from ruminants such as Ostertagia, Haemonchus, Cooperia, Nematodirus, Trichostongylus, Strongyloides, Munostomum, Trichuris, Oesophagostomum, and Chabertia ovina

- Also possess high efficacy against lung worms (Dictyocaulus spp) in sheep and cattle

- Active against most of the parasite spp that affect goats

- Arthropod parasites controlled include mites, oestrid larvae, and sucking lice

- highly efficacious against cattle ticks

- contribute to control of horn fly in cattle

which ML has demonstrated a distinctive 100% protection for 21 days post-infection of the screw worm in calves

Doramectin

which formulations for cattle are highly effective in the control of sucking and biting lice

pour-ons

what are the different endectocide formulations for swine

- SC: ivermectin and moxidectin

- IM: doramectin

- PO feed formulations: ivermectin

what is the spectrum of endectocides in horses

Highly effective against Parascaris equorum, Oxyuris equi, stomach worms, Strongyloides westeri, and lungworms (D. arnfieldi)

which dog breeds are known to be particularly sensitive to ivermectin

collie dogs and some australian shepherds

how is ivermectin used in dogs and cats

effective against 3rd and 4th stages of D. immitis and also used in control of demodectic mange infestations in dogs at higher doses for prolonged regimens

what is milbemycin oxime

known as proheart 6/12 or sentinel which is effective against developmental stages of D. immitis, T. cans, T. leonina, A. caninum, and T. vulpis

what is selamectin used for

a new avermectin compound introduced as a topical formulation for dogs and cats that is highly efficacious against D. immitis, T. canis, T. leonina, A. tubaeforme, and T. cati as well as fleas, mites, and ticks

describe the transporter interaction of ivermectin

- ivermectin is a relatively potent P-GP inhibitor and rather weak BCRP inhibitor

- P-GP mediated interaction increases ivermectin systemic exposure in host and may also decrease efflux transport over-expressed in target resistant nematodes

what are the available preparations of ivermectin

- An oral paste containing 1.87% for horses

- Formulated in a micellar solution for oral drench use in sheep and goats

- Tablet and chewable preparations for oral administration to dogs and cats

what are the available preparations of doramectin

oil-based formulation containing sesame oil/ethyl oleate at a 90:10 ratio for SC or IM to cattle

what are the available preparations of moxidectin

- Pour-on for cattle: zydectin

- Oral for sheep and horses

what are the available preparations of eprinomectin

Topical formulations for beef and dairy cattle

true of false: Eprinomectin and moxidectin pour-on formulations are now indicated in lactating dairy cows with zero milk WD time in some countries

true

Highest tissue residue concentrations of MLs in food animals are recovered from where

liver and fat

Classic 1% injectable cattle formulations of abamectin, ivermectin, doramectin, and moxidectin in food animals require WD times of what

35-50 days

A post treatment period of how long is required to deplete moxidectin below the established tolerance limits for different tissues after its administration as a long acting preparation (10%) in cattle SC injected in base of the ear

84 days

describe the safety of avermectins

- have at least a 10-fold safety margin in all vet spp except collies and some australian shepherds

- signs of toxicity include depression, ataxia, tremors, salivation, mydriasis, and in severe cases, coma/death

describe the safety of milbemycin compounds

- wide therapeutic margin

- No adverse effects have been observed in cattle SC treated with moxidectin up to 10x recommended dose

which other MLs are good substitutes for ivermectin in collies and australian shepherds

Selamectin and milbemycin oxime

what is true of animals deficient in P-GP expression in the intestine

may absorb more drug after oral treatment, which may result in higher blood concentrations and enhanced potential for neurotoxicity

what is the rule of thumb when switching heartworm preventatives

30 day washout period when switching oral heartworm preventatives in order to prevent seizures and death