Control of Ectoparasites

Ectoparasiticides kill ______

• Including ____ and ______

ectoparasites, insects, arachnids

So insecticides kill _____

Acaricides kill ______

Insects, acarhnids

What are the main reasons to control ectoparasites?

• Cause important diseases: e.g. Mange (mites), FAD (fleas), Blowfly Strike (flies)

• Debilitating irritant to host

• Source of infestation - other animals and humans

• Vectors of disease: Ticks, Mosquitoes, Fleas

• Economic loss - reduce yields - downgrading of hides

• Compromise animal welfare

Why are ectoparasites difficult to control?

1. Large seasonal increases in populations

   • Tick population increases in spring/autumn

   • Blowflies increase in late spring and early summer

   • Sheep scab mite (psoroptes ovis) increase winter

2. Infestations can be highly contagious

   • High stocking density - notable

   • Location - transport - close contact

3. Can be widespread in the environment,

   • although some are more localised

What are some basic strategies used to control ectoparasite infection?

Deployment and application of drugs to kill and repel insects and arachnids (all)

• Quarantine and treatment of incoming stock (e.g. scab)

• Farm biosecurity and coordinated treatment (e.g. scab)

• Treatment of all in contact animals (e.g. sarcoptic mange)

• Treatment of the local environment/habitat (e.g. flea allergy dermatitis)

• Treatment of underlying condition (e.g. adult onset pustular demodecosis)

• Vaccines against ectoparasites (Rhipicephalus tick)

Mechanical removal - traps (e.g. tsetse fly) and vacuums (fleas)

Legislation to report and treat infestations/disease (e.g. Scab)

What are the main classes of ectoparasiticides?

• Macrocyclic Lactones

• Isoxazolines

• Phenylpyrazoles (Fipronil)

• Neonicotinoids

• Pyrethrins and Synthetic Pyrethroids (SPs)

• Organophosphates

• Insect Growth Regulators (IGRs)

Reminder** What is selective toxicity?

... is the ability of a chemical or drug to harm an invading organism without harming the host

Target using

• location

• pharmacokinetics

• pharmacodynamics

Reminder** What are key features of the macrocyclic lactones?

• Highly lipophilic → persist for a long time ESPECIALLY if applied topically as it will remain in the fat below the epidermis

• Crosses membrane easily

What is the mechanism of action for Isoxazolines?

e.g. alfoxolaner, fluralaner

Mechanism of action

• Inhibit GABA-gated chloride channels

• Glutamate-gated chloride channels also implicated

• Irreversible hyperexcitation in insects and ticks

• Drug is highly protein bound, ingested by fleas and ticks upon ingesting within hours

Describe the ADME of Isoxazolines.

Absorption:

Is well absorbed from the gastrointestinal tract, no matter what route of entry.

Distribution:

It is very lipophilic, allowing it to distribute widely into body tissues. It has a high volume of distribution (greater than 2.5 L/kg) and is highly plasma protein bound (about 99%).

• High PPB is important so parasite ingests a high concentration through the blood

Excretion:

Elimination is slow due to the high lipophilicity, has a long half-life (2 weeks)

Dosing:

• Afoxolaner is administered monthly, while fluralaner is given every three months.

Describe the selective toxicity of the Isoxazolines. 

• Any Side effects

• Spectrum of Activity

Nature of selective toxicity:

• More selective for GABA- and Glutamate-gated channels in insects and ticks than mammals (More selective for parasite channels than mammals)

Side effects

• Rare

• Vomiting/diarrhoea, lethargy and anorexia

Spectrum of activity

• Fleas, ticks

What is the mechanism of action for the Phenylpyrazoles.

e.g. Fipronil

Mechanism of action

• Non-competitive blockade of GABA-gated and Glutamate-gated chloride channels

• Stopping the “inhibition” → hyperexcitation

Selective Toxicity

• Binding to mammalian GABA-gated channels is less effective

• Mammals do not have Glutamate-gated chloride channels

Describe key features of Phenylpyrazole pharmacokinetics.

• High affinity for oils in the skin due to lipophilic nature

• Following topical application (e.g., a "spot-on" treatment), the compound spreads or "translocates" over the entire surface of the animal's body via the natural movement of skin oils, rather than relying on systemic absorption through the bloodstream.

• Significant deposition in sebum, sebaceous glands and hair follicle, acts as a reservoir for continued release over a long period of time

Describe the key features of the phenylpyrazoles, noting:

• Side effects

• Spectrum of Activity

Side effects

• Wide margin of safety

• At toxic dose hyperactivity, hyperexcitability, convulsions

Spectrum of activity

• Adult fleas, all stages of ticks

• Approved for dogs, cats and puppies/kittens >8weeks

• 30 days (potentially longer)

Describe the mechanism of action for the Neonicotinoids.

e.g. Imidacloprid, Spinosad

Mechanism of action

• Competitive inhibition at nicotinic Acetylcholine receptors

• widely distributed in the insect CNS

• highly specific for the insect nicotinic receptor subtype

Biphasic response

• increased frequency of spontaneous discharge

• followed by a block in nerve pulse propagation

What is the ADME for the neonicotinoids?

• Topical application results in surface translocation over the entire body

• Efficacy as a result of the insect contacting the chemical at the skin surface

• Rapidly absorbed by the insect on contact, limited systemic absorption as most of the drug remains on the skin’s surface

• Limited systemic absorption in host

• Efficacy up to 4 weeks (Due to lipid solubility)

What is the nature of selective toxicity in the neonicotinoids?

• Also note side effects

• Spectrum of activity

Nature of selective toxicity:

• do not bind effectively to mammalian Nicotinic or Muscarinic receptors

Side effects

• Very few reports following dermal exposure

• Nicotinic effects/hepatic effects in studies of oral exposure

• Should not be normal route of administration

Spectrum of activity

• Adult fleas on dogs and cats

• Crop insecticide

Describe the mechanism of action for Pyrethrins and Synthetic Pyrethroids.

Pyrethrins, naturally occurring compounds;

Gradually replaced with synthetic pyrethroids:

• e.g. permethrin, cypermethrin, deltamethrin, flumethrin

Mechanism of action:

• Causes voltage-gated sodium channels to stay open, when normally they need to open and close 

• Slows both the activation and inactivation process

• Channel in a stable hyperexcitable state

Describe the ADME for the Pyrethrins and SPs.

Absorption:

Dermal absorption is very limited due to the drug's high lipophilicity and large molecular weight

Distribution:

The molecules remain mainly in the stratum corneum (outer skin layer) with little or no penetration into systemic circulation.

Metabolism:

Any absorbed portion is rapidly detoxified by the liver and blood.

Excretion:

Metabolites are quickly cleared from the body, minimizing systemic exposure.

What is the nature of selective toxicity in pyrethrins and SPs, as well as the:

• Side effects

• Spectrum of activity

Nature of selective toxicity:

• Rate of metabolism of the compound is more rapid in vertebrates, and has very limited absorption via topical application to have any adverse effects

• Selective for insect voltage-gated sodium channels

Side effects

• Dermal exposure rarely causes toxicity

• BUT grooming can result in significant oral ingestion - life threatening for cats!

• Tremors, twitches, hyperthermia, seizures

Spectrum of activity

• Application varies

• Shampoos, sprays, collars, dips, dusts, ear tags to repel or treat most known ectoparasites

• Also reported to be a good repellant 

What is the mechanism of action of the Organophosphates?

e.g. Diazinon

Mechanism of action - Anti-ectoparasitic drugs, also used as antithelmentic drugs, but safer drugs exist

• Irreversible inhibition of acetylcholinesterase

• Accumulation of acetylcholine leads to overstimulation, paralysis and death of the parasite

**Because acetylcholinesterase breaks down acetylcholine, inhibiting it makes acetylcholine build up

Describe the ADME of the organophosphates?

Absorption:

Applied topically as a dip (formerly also in shampoos, collars, sprays, and dusts).

Distribution:

Primarily remains on the skin and hair coat with minimal systemic absorption.

• Allows it to become absorbed by the parasite

Metabolism:

Metabolized in the mammalian liver by hydrolysis.

What is the nature of selective toxicity in the organophosphates, also noting:

• Side effects

• Spectrum of Activity

Nature of selective toxicity

• Less selective for mammalian AChE

• More readily metabolised by mammals

• But:

• Risk of significant toxicity

• Restrictions on use - certificate of competence required

Side effects

• More pertinent to handlers of animals than the handler themselves

  • Autonomic (muscarinic) effects

  • Nicotinic effects (NMJ)

  • CNS

  • Drug interactions 

Spectrum of activity

• Insecticidal, ascaridicidal, helminthicidal (Broad spectrum parasiticide) 

  • Primary use in UK - treatment of sheep scab (mobile operators)

  • Require a special license to work with this drug

Describe the mechanism of action and any notes for Insect Growth Regulators:

• Juvenile Hormone Analogies

• Insect Development Inhibitors

• Cyromazine / Dicylanil

• They are not “killing” the parasite, they target early stages of development and impede maturation into adulthood

Why is there significant concern about the environmental impact of ectoparasiticides?

• Environmental Impact → Veterinary use contaminates environment and kills insects in the environment

• Impacting populations necessary for ecosystem health