LEC 25 - Macrocyclic Lactones Flashcards
What do macrocylic lactones work against?
Nematodes and ectoparasites
What are macrocyclic lactones made from?
Streptomyces spp.
What are the two major groups of macrocyclic lactones?
Avermectins and milbemycins
What avermectins are used in food animal?
Ivermectin, eprinomectin, and doramectin
What avermectins are used in small animals?
Selamectin and ivermectin
What avermectins are used in horses?
ivermectin
What mibemycins are used in food animal?
Moxidectin
What mibemycins are used in small animals?
Moxidectin and milbemycin oxime
What mibemycins are used in horses?
Moxidectin
How do macrocyclic lactones work?
Activate two ligand-gated, chloride channels. Glutamate-activated, chloride channel. GABA receptor.
What happens when macrocyclic lactones activate glutamate-activated chloride channels?
Hyperpolarizing. Flaccid paralysis of somatic musculature and pharyngeal pump. Inhibition of reproductive tract in female nematodes.
Is the action of macrocyclic lactones reversible or non-reversible at the chloride channels?
non-reverisble
Where are GABA receptors found in nematodes?
Ventral nerve cord and head
What is the difference about ML’s effects on gaba receptors compared to chloride receptors?
Need high concentrations of the drug to effect GABA receptors therefore probably the reason for ML’s adverse effects.
How are ML’s adminstered?
SC, IM, PO, and topical(w/ secondary oral)
What is the absorption like in ruminants for ML’s?
Highly lipophilic drugs are poorly absorbed in ruminant GI tract.
How long do formulations of ML’s last?
135days
Where do ML’s distribute to?
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.
How are ML’s metabolized?
Oxidation in the liver.
How are ML’s eliminated?
95% fecal and 5% urine (as parent compound)
What is the process of enterohepatic recycling that occurs with ML’s?
20% of metabolites, parent compounds. Leads to prolonged effects of the drug
Where are avermectins eliminated from?
Milk, therefore use is restricted in non-lactating animals. The exceptions to this are eprinomectin and moxidectin.
What is P-gp?
ATP-dependent, broad specificity efflux pump
What another names does p-gp go by?
MDR1, ABCB1, or CD243
Where is p-gp expressed in the mammalian body?
Brain capillary endothelium, SI epithelium, biliary canalicular cells, renal proximal tubular cells, and placenta/testes
What three places of p-gp expression are important to ML’s excretion?
Brain, Small intestine, and biliary system
What mutation occurs in collies? What is it’s effects?
4bp, inactivating deletion. Homozygotes have a non-functional P-gp. Ivermectin levels in brain increase dramatically. Then lead to activation of GABA receptors.
What are the ten breeds of dogs that are most likely to have the MDR1 mutation?
Collie, longhaired whippet, shetland sheepdog, miniature australian shepherd, silken windhound, McNab, Australian shepherd, Waller, White swiss shepherd, and old english sheepdog.
What are the signs of toxic effects of ML’s?
Vomiting, tremors, ataxia, mydriasis, blindness, and seizures
When do OD signs from ML’s appear in cats?
10 hours from time of ingestion. But safe at 30x’s the normal cat dose. For kittens it is 4x’s the cat dose.
How much ML does it take to see signs of toxicity in horses?
9 to 10x’s the dose
How much ML does it take to see signs of toxicity in cattle?
~12 x’s the dose
How much ML does it take to see signs of toxicity in adult pigs?
100 x’s the dose
When do you see hypersensitivity with ML adminstration?
With large worm burden
How much ML does it take to see signs of toxicity in a wildtype dog?
160x’s the dose, death will occur at 6,000 x’s the dose
How much ML does it take to see signs of toxicity in a ABCB1 mutant dog? How long does it take to see?
What is a safe alternative with ML’s in collies?
Milbemycin oxime, because it does not cross the BBB. Selamectin would also work because it has a much higher toxic dose.
What drug acts with ML’s to increase BBB permeability?
Spinosad
What is ivermectin used for in dogs?
Dirofilaria (heartworm), sarcoptes scabiei, Otodectes, Demodicosis, Cheyletiella, Pneumonyssus (nasal mites)
What is selamectin used for in dogs?
Heartworm, Fleas, Otodectes, Sarcoptes scabiei, Dermacentor variablilis
What is milbemycin oxime used for in dogs?
Dirofilaria immits, GI roundworms, Hookworms, and whipworms
What is moxidectin used for in dogs?
Heartworm and hookworms
What three ML’s are used in cats?
Ivermectin, selamectin, and milbemycin oxime
What is ivermectin used for in cats?
heartworm
What is selamectin used for in cats?
heartworm, fleas, otodectes, T. cati, and A. tubaeformae
What is milbemycin oxime used for in cats?
Heartworm, GI roundworms, and hookworms
What is the lifecycle of a heartworm?
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.
How long do heartworm live in dogs?
Adults, 5 to 7 years. Microfilariae 1 to 2 years.
How long do heartworm live in cats?
Adults, 2 to 4 years. MIcrofilariae rarely circulate.
Class 1 Heartworm Infection -
Asymptomatic, (+) antigen test
Class 2 Heartworm Infection -
Moderate Pulmonary Damage with coughing and excercise intolerance.
Class 3 Heartworm Infection -
Right CHF, syncope, anemia, cachexia, and cor pulmonale
Class 4 Heartworm Infection -
Class 3 along with shock, DIC, jugular distention, and mitral regurgitation
What is Wolbachia?
Obligate, intracellular, gram (-), bacteria/rickettsia
What is Wolbachia associated with?
Survival/production/infectivity of filaria along with pulmonary and renal inflammation due to WSP surface proteins
What drug can kill Wolbachia?
Doxycycline
What is the recommendation protocol for heartworm treatment in regards to Wolbachia?
Treat with doxycycline for 30 days prior to melarsomine. Reduces worm burden prior to adulticide.
What is done if for whatever reason there is a contrindication for melarsomine use?
Use doxycylcine alone as sole adulticide in dogs
What does it mean when you get a (+) heartworm test?
30+ adult female worms
What is the DOC for heartworm treatment?
Melarsomine
How is melarsomine adminstered?
IM
What do you have to worry about when giving melarsomine?
Pulmonary thromboembolic events and hypersensitivity reactions
What is melarsomine contraindicated in?
Dogs with Caval Syndrome
Where does ivermectin work in the heartworm lifecycle?
L3/4, while the larvae is in the tissue phase
What two ML’s are used in pigs?
Ivermectin and doramectin
What is ivermectin used for in pigs?
GI roundworms, lungworms, lice, and sarcoptic mange
What is doramectin used for in pigs?
as indicated
What two ML’s can be used in horses?
Ivermectin and moxidectin
What is ivermectin used for in horses?
Gastrophilus intestinalis
What is moxidectin used for in horses?
Cyanthostomum sp.
Where do you see invermectin resistance?
Haemochus in sheeps and goats. Trichostrongylus in cattle.
What drug is being looked into as an additive to ML’s to combat resistnace? Why?
Verapamil, reverses P-gp
What is thought to be the mechanism behind resistance to ML’s ?
Increased expression of P-gp
