Antinematodal Drugs Flashcards
What are 5 aspects of an ideal antiparasitic?
- wide therapeutic index where the toxic dose is at least 3x the therapeutic dose
- effective (after one dose) in removing parasites from body
- easy to administer
- inexpensive
- does not leave residues important in food-producing animals
What 3 things should be considered when using antiparasitics?
- development of resistant strains
- inhibition of host immunity
- cost
What are the main 3 mechanisms of action of most antiparasitic agents?
- paralysis of parasites by mimicking the action of putative neurotransmitters
- alteration of metabolic processes
- alteration of parasite reproduction
What are the 2 main results of antiparasitics mimicking neurotransmitters? What does this allow for?
- mimics the action of excitatory transmitters = spastic paralysis of parasite
- mimics the action of inhibitory transmitters = flaccid paralysis of parasite
allows normal peristaltic action of host to expel the parasite
What are 6 general mechanisms antiparasitic drugs use to alter metabolic processes of parasites?
- inhibits microtubule synthesis
- inhibits folic acid synthesis or metabolism
- inhibits thiamine utilization
- uncouples oxidative phosphorylation
- inhibits chitin formation in arthropods
- stimulates insect juvenile hormones to block metamorphosis
In what 2 ways do antiparasitic drugs alter parasite reproduction?
- inhibits replication in protozoans
- inhibits egg production in nematodes
What are 3 common factors that may be responsible for antiparasitic drug failure?
- incorrect use of anthelmintic drugs due to insufficient knowledge of their pharmacological features
- insufficient understanding of the relationship between pharmacological properties and host-related factors
- indiscriminate use accounts for widespread development of drug resistance
What is the mechanism of action of benzimidazoles and probenzimidazoles?
binds parasitic β-tubulin and blocks its polymerization to α-tubulin, which usually forms part of the cytoskeleton and provides structure to cells
misformed microtubules alters cell division, maintenance of cell shape, motility, and secretion, nutrient absorption, and intracellular transport
What are the 3 classes of benzimidazoles?
- EARLIER BZD THIAZOLYLS = thiabendazole, cambendazole
- BZD METHYLCARBAMATES = parcendazole, mebendazole, flubendazole, oxibendazole, luxabendazole, albendazole, fenbendazole, oxfendazole
- HALOGENATED BZD THIOLS = triclabendazole
What is the therapeutic use of halogenated benzimidazole thiols?
triclabendazole = flukicidal activity against all stages of Fasciola hepatica
What 3 pro-benzimidazoles are commonly used? What are they metabolized into? Where does this metabolism happen?
- thiophanate —> lobendazole, liver
- febantel —> fenbendazole, liver
- nectobimin —> albendazole, reduced in the GIT
What is the appropriate site for dissolution of benzimidazoles after oral treatment? Why?
stomach/abomasum - aqueous solubility is markedly higher at lower pH
What is the spectrum of action of benzimidazole methylcarbamates?
broad-spectrum anthelmintic active against a variety of GI and lung nematodes, tapeworms, and trematodes
What 4 benzimidazoles are commonly used in ruminants? What are their 2 therapeutic uses? What are they ineffective against?
albendazole, fenbendazole, albendazole sulfoxide, oxfendazole
- GI worms (larvae and adults)
- lungworms
filariae
What 3 benzimidazoles are commonly used in horses? What 4 groups of parasites are the most effective against? What 2 are they ineffective against?
fenbendazole, oxfendazole, oxibendazole
- strongyles
- Oxyuris
- Trichostrongylus
- Parascaris
- migrating larvae of Strongylus vulgaris and Strongylus edentatus
- Gasterophilus
What 3 benzimidazoles are commonly used in companion animals? What 3 species are they most effective against?
febantel (pro-BZD), fenbendazole, mebendazole
- ascarids (Toxocara spp.)
- hookworms (Ancyclostoma caninum)
- whipworms (Trichuris vulpis)
- both adult and larval forms
What 2 benzimidazoles are commonly used in poultry and pigs? What are they most effective against?
fenbendazole, flubndazole
- large roundworms (Ascaris)
- nodular worms (Oesophagostomum)
- lung worms (Hyostrongylus, Metastrongylus)
- whipworms (Trichuris)
- kidney worms (Stephanurus)
Benzimidazoles:
What does the anthelmintic activity of benzimidazoles depend on? What is an important limitation of the formulation?
ability to reach high and sustained concentrations at the parasite location
lack of water solubility - suspension, past, granules, tablets, blocks, powder feed administration, pellets
What is a common inconvenience of the systematic availability of enterally administered benzimidazoles? What are 2 causes?
poor/erratic GI absorption
- mucous surface in GIT acts as a lipid barrier for absoprtion
- drug particles must dissolve in enteric fluids to facilitate absorption - undissolved = excreted in feces
What are the 2 mechanisms of benzimidazole entry into parasites? What does this depend on?
- external surface of nematodes (cuticle)
- external surface of cestodes/trematodes (tegument)
lipophilicity
What are the 3 most and least lipophilic benzimidazoles?
fenbendazole, albendazole, mebendazole
oxfendazole, albendazole sulfoxide, thiabendazole
What are the major mechanisms of drug transfer into nematodes, cestodes, and trematodes?
NEMATODES and CESTODES = passive diffusion through cuticle/tegument
TREMATODES = oral ingestion
What 5 characteristics affect diffusion of anthelmintics across the cuticle and tegument of nematodes and cestodes?
- drug lipophilicity
- drug ionization
- concentration gradient
- composition of the parasite’s environment
- parasite’s external surface
What 3 parasites are able to biotransform anthelmintic drugs? How do they do it?
- Fasciola hepatica - oxidates albendazole into sulfoxide derivatives
- Haemonchus contortus - biotransforms albendazole into different albendazole glucoside metabolites
- tapeworms - sulforeduction of albendazole sulfoxide into its parent sulfide compound
What is thought to facilitate the accumulation of anthelmintics into the parasites?
partitioning of the active drug and metabolites between an aqueous GI fluid and the lipoidal tissue
How does the ruminal esophageal groove affect the efficacy of benzimidazole anthelmintics?
the ruminoreticulum is usually the first enteric chamber encountered by orally administered drugs, but upon its closure, ingested fluids may partially bypass is and enter the abomasum
- this causes variable portions of the drug solution/suspension to become divided
What 2 classes of drugs are mostly affected by ruminal esophageal groove closure?
- compounds activated in the rumen
- benzimidazoles with low solubility in abomasal fluid
How does a delayed GI transit time affect anthelmintics?
decreases the rate of passage of the drug down the GI tract, giving drugs more time to dissolve and absorb in the proper place
- feed restriction/fasting enhances plasma levels of anthelmintics
What fluke commonly affects the liver? How is it able to affect the efficiency of anthelmintics?
Fasciola hepatica
causes liver disease/damage that reduces the enzymatic activity of different microsomal oxidases
What species is the use of benzimidazoles contraindicated in?
horses to be slaughtered for food purposes
- check label instructions of each formulation concerning withdrawal times before use!
What 5 benzimidazoles have been reported to be teratogenic? How does this affect their use?
- Parbendazole
- Cambendazole
- Oxfendazole
- Febantel
- Albendazole
limits their use in the early stages of pregnancy
True or false: Regarding the mechanism of drug transfer into target parasites, oral ingestion is the main route of drug entry into nematode parasites.
FALSE - passive diffusion
When using BZDs drugs what are the aspects you have to consider? Select all correct answers.
a. poor solubility in water
b. narrow margin of safety
c. teratogenic effect
d. effective only against nematodes
c. they are prodrugs
A, C
