Anthelmintics Flashcards
Broad-spectrum anthelmintic
drug classes
- macrocyclic lactones
- benzimidazoles / pro-benzimidazoles
- pyrimidines
origin and subgroups of macrocyclic lactones
- origin = natural fermentation products of streptomycetes
- two subgroups:
a) avermectins
b) milbemycins
Macrocyclic lactones:
types of avermectins:
- ivermectin
- doramectin
- eprinomectin
- selamectin
Macrocyclic lactones:
types of milbemycins:
- milbemycin
- moxidectin
macrocyclic lactones spectrum of activity? what is it not effective against?
- broad spectrum activity (“endectocides”):
> nematodes (e.g. hookworms, Ostertagia)
> arthropods - insects (e.g.lice,bots)
- mites (e.g. Chorioptes, Otodectes)
No activity against cestodes, trematodes & protozoa
macrocyclic lactones effective at what dose? safety profile and withdrawl? cost?
- highly effective at low dosages (mcg/kg body weight)
- some have zero meat / milk withdrawal time
- generally wide safety margin
- BUT - expensive
mechanism of action of macrocyclic lactones
- bind with high affinity to glutamate-gated Cl- channels (invertebrate nerve and muscle cells)
> increase membrane permeability to Cl- ions
> hyperpolarization of nerve / muscle cell - bind to GABA-gated Cl- channels:
- nematodes + arthropods > synapses between nerves and nerve/muscle cells
- stimulates GABA release
- enhances postsynaptic binding of GABA
(GABA = inhibitory neurotransmitter)
Low toxicity of macrocyclic lactones is due to:
- Mammals do not have glutamate-gated Cl- channels.
- GABA receptors in central nervous system of mammals
- Macrocyclic lactones do not readily cross the blood-brain barrier:
> P-glycoprotein expressed by brain endothelial cells > drug efflux from CNS - Macrocyclic lactones have a low affinity for other ligand-gated Cl- channels.
(affinity for invertebrate receptors = 100x mammalian receptors)
ivermectin - history and origins
- first macrocyclic lactone developed for commercial use
- natural fermentation product of Streptomycetes avermitilis
- chemically modified (“semisynthetic”)
Ivermectin formulations
- Oral
- liquid / drench
-chewable
- feed premix
- paste - Injection - liquid
- topical - pour-on solution
Ivermectin toxicity; who is susceptible ?
- multi-drug resistance gene (MDR1) - encodes P-glycoprotein efflux pump in blood-brain barrier
- some dog breeds - mutation of MDR1: decreased ability to pump ivermectin out of CNS
- breeds affected:
- 3 out of every 4 Collies in USA
also - Shetland Sheepdogs
- Australian Shepherds
- Old English Sheepdogs
- German Shepherds
- Long-haired Whippets
- Silken Windhounds
ivermectin toxicity: symptoms
Dogs:
Acute toxic syndrome: mydriasis, depression, tremors, ataxia, stupor, emesis, salivation, coma
what dosage of ivermectin is toxic? vs the licensed dose
What dosage is toxic ?
* licensed dosage = 0.006 mg/kg (heartworm prevention)
* toxic dosage in Collies = 0.1 mg/kg
* Demodex dosage = 0.4-0.6 mg/kg/day
how do you know if a collie is susceptible to ivermectin toxicity?
cheek brush sample > genotype
macrocyclic lactones used in dogs and cats? which are licensed as safe in collie breeds?
- ivermectin, milbemycin, moxidectin, selamectin
- eprinomectin (cats only)
- moxidectin & selamectin = licensed as safe in Collie breeds
macrocyclic lactones used in cattle
- ivermectin, doramectin, eprinomectin
macrocyclic lactones used in pigs
- ivermectin, doramectin
macrocyclic lactones used in horses
- moxidectin > not licensed for foals <4 months due to low therapeutic index
- ivermectin
drug resistance to macrocyclic lactones is a problem for which parasites in dogs (and where)?
- Dirofilaria immitis - USA
- Ancylostoma caninum - USA/Canada?
drug resistance to macrocyclic lactones is a problem for which parasites in sheep (and where)?
- Haemonchus sp.
- teladorsagia sp.
> USA, Canada, and globally
drug resistance to macrocyclic lactones is a problem for which parasites in horses (and where)?
- Parascaris equorum > USA, Canada & globally
- cyathostomins > Brazil, Europe, (& USA)
drug resistance to macrocyclic lactones is a problem for which parasites in cattle (and where)?
- Cooperia sp. > USA, Canada, and globally
- Ostertagia sp. > USA, Canada, and globally
types of benzimidazoles
- fenbendazole
- albendazole
- febantel = pro-benzimidazole
activity of benzimidazoles
Active against large number of nematodes, flukes, some tapeworms and some protozoa (e.g. Giardia).
mechainism of benzimidazoles
- bind to beta-tubulin
> inhibit polymerisation to microtubules:
> inhibit cell division, glucose uptake, parasite motility
benzimidazoles administration strategy
- administered orally > poor absorption
> absorption increases if ingested with a fatty meal - optimal efficacy normally only observed after repeated doses
benzimidazoles toxicity profile
- relatively non-toxic <-> poor systemic availability
- rapidly dividing cells potentially at risk:
- haematopoetic stem cells (eg. albendazole in dogs)
- some have teratogenic potential in early stages of pregnancy (eg. albendazole in cattle and sheep)
what animals in fenbendazole used in? what is its off-label activity?
- dogs, horses, cattle, pigs, poultry (sheep)
- common off-label activity = giardia
drug of choice for foals with large burden of Parascaris equorum
fenbendazole
albendazole used in which species? spectrum of activity vs others? issues with its use?
- cattle, (sheep)
- benzimidazole with broadest spectrum of activity
- potentially teratogenic – don’t use in first trimester
- uncommonly associated with bone-marrow toxicosis in dogs
febantel is used in what animals?
dogs only (Note: toxic for cats)
what happens to febantel in the liver?
biotransformed in liver > fenbendazole + oxfendazole
febantel is given with what? why?
- co-administration with pyrantel (Drontal Plus)
- synergizes activity of pyrantel > Trichuris vulpis
benzimidazoles resistance issues in sheep? where?
Sheep – Haemonchus +Teladorsagia - globally
benzimidazoles resistance issues in horses? where?
Horses – cyathostomins - globally
benzimidazoles resistance issues in cattle? where?
Cattle – Cooperia + Ostertagia – globally
benzimidazoles resistance issues in dogs? where?
Dogs – Ancylostoma caninum – USA/Canada?
what pyrimidines are used, and in what animals?
- pyrantel pamoate (dogs, cats, horses)
- pyrantel tartrate (pigs)
what are pyrimidines effective against?
Active against large number of nematodes (e.g. Toxocara, cyathostomins,Ascaris) & horse tapeworm
mechanism of action of pyrimidines
- “nicotinic anthelmintic”
- act selectively on parasite nicotinic acetylcholine receptors:
- acetylcholine agonist + inhibition of acetylcholinesterase > depolarisation > paralysis > expulsion
pyrantel administration and consequences of its properties
- only administered orally
- cat dosage = 4 x dog dosage
- pyrantel pamoate:
- low aqueous solubility > low systematic availability > increased margin of safety > increased efficacy against gut parasites
contraindications for pyrantel
efficacy decreased if administered to animals with diarrhea
resistances to pyrantel for horse and dog parasites, and geographic range
- Horses – cyathostomins – globally, especially USA
(availability of daily in-feed product = Strongid C) - Dogs – Ancylostoma caninum – Australia, USA/Canada?
parasites with drug resistances of greatest concern for macrocyclic lactones, benzimidazole, and pyrimidine
Dirofilaria immitis - macrocyclic lactones
Ancylostoma caninum - macrocyclic lactones, benzimidazole, pyrimidine
Cyathostomins - (macrocyclic lactones), benzimidazole, pyrimidine
