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.

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