Anthelmentics Flashcards
how can nematodes be transmitted
ingestion from contaminated material
contaminated water
intermediate host
direct invasion through skin
what is a broad spectrum antihelmentic
benzimidazoles
what are the narrow spectrum antihelmentics
avermectins
milbemycins
ivermectin
how do most antihelmentics act on parasites
by acting on their CNS/neuromuscular systems
what is not an ionotropic receptor
GABA-B receptors
they are G-protein coupled receptors
what have been the main approaches used to study the pharmacology of anthelmentics
pharmacological studies in model nematodes
genetic studies in C. elegans
how does lemavisole affect nematodes
causes spastic paralysis
what is the mechanism of action of lemavisole in C. elegans
acts on nicotinic acetylcholine receptors
what is an advantage of using C. elegans
it is a self-fertilising hermaphrodite
how was the physiochemical effect of lemavisole and what does it show
a patch clamp was used
typical ACh currents were observed under lemavisole
shows its a ACh agonist
how is lemavisole absorbed in the host
absorbed across the gastro-intestinal tract
what are the side-effects of lemavisole and why they might be
usually well tolerated by the host
nausea/dizziness
probably due to activation of nicotinic receptors at the autonomic ganglia
what is the selective toxicity of lemavisole
relies on difference between host and parasitic nicotinic acetylcholine receptors
weak agonist of neuromuscular junction receptors
how was the selective toxicity of lemavisole tested
the cDNA of mass nicotinic acetylcholine receptor subunits was injected in xenopus oocytes
they then express the receptors on their surface
can then be used for electrophysiological experiments - measure the sensitivity of lemavisole to those reseptors
what is the effect of piperazine on nematodes and its proposed mechanism of action
causes flaccid paralysis
probably due to its similar structure to GABA - GABA agonist
why can use of GABA cause piperazine to not work
cross-sensitivity of GABA and piperazine can cause the tissue to become desensitised
how is piperazine absorbed in the host
well absorbed through the gastro-intestinal system
what are the side effects of piperazine
usually well tolerated by the host
nausea/vomiting
contraindicated for epilepsy
why is a contraindication of piperazine epilepsy even though it is a GABA (inhibitory) mimetic
piperazine is a partial agonist of GABA-A
partial agonists can act antagonists
further compromises an epileptic brain’s inhibitory mechanisms
what is ivermectin
macrocylic lactone
semi-synthetic derivative of a natural compound
what is ivermectin in/effective at targeting
effective only at targeting filarial nematodes and microfilariae
ineffective at targeting cestodes/trematodes
what effects does ivermectin have on nematodes
paralysis
inhibits feeding
inhibits egg-laying
what made ivermectin a breakthrough
it was resistance breaking
treated resistant nematodes
what is the mechanism of action of ivermectin
very potent action
little effects on mammalian system
inhibits insect muscle by opening chloride channels
how was the mechanism of action of ivermectin studied and measured
dissected locust muscle tissue
placed in physiological saline solution
impaled the tissue with 2 glass microelectrodes connected to amplifiers
one was used to record membrane potential and the other to inject currents
what cDNA produced a response to glutamate
GluCl-beta
what cDNA responded to ivermectin
GluCl-alpha
what insight on what receptor ivermectin acts on did iterative screening give us
that the receptor is most likely composed of an GluCl-alpha subunit which binds to ivermectin and a GluCl-beta subunit that binds glutamate
leads to chloride mediated hyperpolarisation
what type of receptor is the ivermectin receptor
it is a glutamate-gated chloride channel consisting of 5 subunits of the GluCl-alpha/beta
why is ivermectin very effective against nematodes but not mammals/vertebrates
glutamate-gated ion channels exist in the invertebrate phyla but not in mammals/vertebrates
what is emodepside
a new generation anthelmentics
resistance breaking - able to treat ivermectin resistant nematodes
what are the effects of emodepside on C. elegans
inhibits locomotion
inhibits feeding
inhibits egg-laying
slows development
what mutation is resistant to emodepside
ion channel mutation on chromosome V
several candidate genes including slo-1
slo-1 -/- are highly resistant to emodepside
what is slo-1
a calcium-activated K+ channel
name a new generation anthelmentic
amino-aceto-nitrile derivatives (AAD’s)
they have drug-breaking resistance properties
how do AAD’s affect C. elegans
inhibit motility
what do AAD’s target
nicotinic acetylcholine receptors
only found in invertebrates
