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57 terms

Anthelmintics

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Anthelmintic
A chemotherapeutic agent used to control helminth infections
Chemotherapy
Use of drugs to injure an invading organism without injury to the host
Anthelmintic Classification
1. Spectrum of Activity
2. Chemical group/Mode of Action
3. Target Parasites
4. Method of Delivery/Formulation
Broad spectrum anthelmintic groups
Group 1: Benzimidazoles (white drench)
Group 2: Imidazothiazoles (yellow drenches)
Group 3: Macrocyclic lactones (clear drenches)
Group 4: Amino acetonitrile Derivatives
Group 5: Spiroindoles
Narrow Spectrum Anthelmintics
Salicylanilides, Substituted phenols: fluke drenches
Pyrazinoisoquinolines, Phenylisothiocyanates: tapewormers
Arsenicals: heartworm
Depsipeptides, COPDs
Piperazines
How do anthelmintics kill worms?
1. Energy metabolism
2. Neuromuscular coordination
3. Cell membrane permeability
Benzimidazole mode of action
They bind to parasite tubulin, leading to an inhibition of glucose uptake, glycogen depletion and ultimately death. Low water solubility, so oral products only
Types of benzimidazoles
Fenbendazole
Mebendazole
Oxfendazole
Albendazole
Triclabendazole
Target Parasites for Benzimidazoles
Nematodes: gutworms (effective against adult, mucosal larvae and hypobiotic larvae), and lungworms
Limited activity against trematodes, cestodes, and protozoa (some active against Giardia).
Pharmacokinetics of Benzimidazoles
BDZs kill worms very slowly
Triclabendazole spectrum of activity
Unique! High activity against Fluke, no activity against nematodes.
Potency of Benzimidazoles
1. Multiple low doses are more potent than a single large dose
2. Potency greater in the ruminant and horse than in the dog/cat (rumen/cecum acts as a reservoir)
3. Potency greater in ruminantes if starved for 12 to 24 hours prior to dosing
Imidazothiazoles/tetrahypropyrimazines mode of action
Cholinergic agonists; causes a rapid and reversible spastic paralysis
Target Parasites for Levamisole
Nematodes: gutworms (not effective against hypobiotic larvae) and lungworms
Pharmacokinetics of levamisole
Most potent is pour-on, followed by oral (reaches highest plasma concentration at 8 hours), and injection has shortest half-life in the body.
Types of macrocyclic lactones
avermectins, milbemycins
Mode of action of macrocyclic lactones
Open invertebrate specific glutamate-chloride channels in postsynaptic membrane leading to flaccid paralysis
Types of avermectins
Abamectin
Doramectin
Eprinomectin
Ivermectin
Selamectin
Types of milbemycins
Moxidectin
Milbemycin oxime
Target Parasites for Macrocyclic Lactones
Nematodes (gut worms and lungworms)
Arthropods (variable activity depending on host and parasite species)
Pharmacokinetics of macrocyclic lactones
Lipophilic, so lasts a long time in the body. Both oral/injection and pour-on will last over 30 days in the body. Persistent effect provides period of protection against re-infection.
Metaphylaxis
Protection of animals grazing contaminated pasture
Prophylaxis
Preventing pasture infection
Benzimidazoles active against nematodes
Albendazole
Fenbendazole
Flubendazole
Mebendazole
Oxfendazole
Ricobendazole
Macrocyclic lactones active against nematodes
-Avermectins
Doramectin
Eprinomectin
Ivermectin
Selamectin
-Milbemycins
Milbemycin oxide
Moxidectin
Yellow Drenches active against nematodes
Levamisole
Pyrantel
Narrow spectrum active against nematodes
Depsipeptides (emodepside), salicylanilides (closantel), piperazines (piperazine), phynylisothiocyanates (nitroscanate)
Benzimidazoles active against Cestodes
Albendazole
Fenbendazole
Flubendazole
Mebendazole
Oxfendazole
Ricobendazole
Yellow Drenches active against cestodes
Pyrantel
Narrow spectrum active against cestodes
Isoquinolines (Praziquantel, Epsiprantel)
Phenylisothiocyantes (nitroscanate)
How does praziquantel work?
Causes tegument destruction (specifically at the proliferation zone). Increased membrane permeability for calcium ions, loss of intracellular calcium, leading to spastic paralysis and malabsorption.
Types of trematocides
AKA flukicides; salicylanilides (closantel, oxyclozanide) and subsituted phenols (nitroxynil)
Pharmacokindetics of salicylanilides
Bind to plasma proteins, giving them a prolonged plasma half-life.
Anthelmintic resistance
When a parasite can tolerate anthelmintic doses which are normally lethal; the ability to do so is heritable.
Resistance
The ability of a parasite population to tolerate doses of a drug that would prove lethal to the majority of individuals within the population
Selection for resistance
Occurs on exposure to anthelmintic and has a genetic basis
Selection pressure
The intensity of the selection process
Side resistance
Resistance to compounds with the same mode of action
Multiple resistance
Resistance to two or more compounds
Reversion
Return to susceptibility
Counter selection
reversion hastened by use of alternative mode of action compound
How does resistance appear?
Resistance alleles pre-exist in most worm populations; when anthelmintic is used, the very few worms with resistance are favored. As allele frequency increases, so does resistance.
What factors influence the rate of AR development?
1. Relative size of the in-refugia population
2. Frequency of treatment
3. Rate of re-infection after dosing
4. Dose rates
If there is a large in-refugia population, will AR develop faster or slower?
Slower.
When an entire group of sheep is treated prior to a move to a low-contamination pasture, the in-refugia population is relatively ___1___ and the selection pressure __2__.
1. small
2. high
What will more frequent treatment do to AR?
Selects faster for AR
When is treatment particularly selective?
When frequency approaches the pre-patent period (i.e. 3 weeks), treatment becomes particularly selective.
What is the effect of under-dosing?
Encourages a rapid appearance of AR
Allows heterozygous parasites to survive
What can be done to delay AR?
Rotations of anthelmintics
Combinations of anthelmintics
Prevent the entry of resistant worms onto farms from other farms
How is resistance measured?
In vivo: drench test, faecal egg count reduction test
In vitro: laboratory-based larval development assays
Drench Test
Quick indicator of anthelmintic efficacy; FEC on 10 fecal saples post treatment. The time after treatment depends on the anthelmintic used (LV 7 days, BZ 10-14 days, ML 14-16 days).
Fecal Egg Count Reduction Test
Estimation of efficacy by coparing FEC before and after treatment with untreated controls. Resistance indicated if treatment does not reduce FEC by >95%.
Larval Development Test
Assess effects of drugs at different concentrations on the development of L1 to L3.
Anthelmintic resistance in Sheep
Southern Hemisphere: Haemonchus worms involved
Australia and New Zealand: multiple resistance common in Teladorsagia and Trichostrongylus
GB: BZ resistance now widespread, increasing reports of resistant Teladorsagia circumcincta.
Anthelmintic resistance in goats
Nematodes commonly reported as resistant in many countries. Also, NO licensed anthelmintics for goats, all off-license use. Sub-optimal dosing therfore common and selects heavily for resistance.
Anthelmintic resistance in cattle
Much less common than with small ruminants, reports mainly from Australia and New Zealand.
Cooperia and some Ostertagia reports.
Few reports of ML-resistant Cooperia in GB
Anthelmintic resistance in horses
Benzimidazole resistance no widespread in cyathostomins both in GB and worldwide.
Resistance to pyrantel and macrocyclic lactones still uncommon.