Internal Parasites

• Arthropods:
• Insects - Bots, grubs
• Helminths:
• Nematodes (roundworms)
• Cestodes (tapeworms)
• Trematodes (flukes)
• Protozoa: Giardia, Sarcocystis, Eimeria, Toxoplasma, Trichomonas, Babesia, Cryptosporidium

Ectoparasites

• Arthropods:
• Insects: Mosquitoes, flies, fleas, keds, lice
• Arachnids: Ticks, mites
• Helminths
• Nematodes (roundworms)

Spectrum of Activity for Neurotoxins

External Parasites

Helminths

Spectrum of Activity for Development Inhibitors

Ectoparasites

Spectrum of Activity for DNA inhibitors

Ectoparasites

Helminths

Protozoa

Spectrum of Activity for Energy Metabolism Inhibitors

Helminths

Protozoa

Spectrum of Activity for Protein Synthesis Inhibitors

Protozoa

Spectrum of Activity for Membrane Inhibitors

Protozoa

Ectoparasites are susceptible to what mechanisms?

Neurotoxins

Development Inhibitors

DNA Inhibitors

Helminths are susceptible to what mechanisms?

Neurotoxins

DNA Inhibitors

Energy Metabo Inhibitors

Protozoa are susceptible to what mechanisms?

DNA Inhibitors

Energy Metabo Inhibitors

Protein Synthesis Inhibitors

Membrane Inhibitors

Resistance to Antiparasitics

• Chromosomal mutations that result from prolonged use of antiparasitics with similar mechanisms of action
• 9-10 parasite generations are required for population to develop resistance to particular type of antiparasitic
• Once resistant, parasites no longer susceptible to any aget within particular group of drugs
• Introduction of animals infested with resistant parasites result in further transmission to new hosts

Methods of detecting resistance to antiparasitics

• Egg/larval counts:
• Can be applied to host and/or environment
• Can do before/after treatment
• One time evaluation for overall assessment of efficacy of a current anthelmintic program
• Regular interval evaluations for efficacy of current program
• Monitoring infection rate
• Examining each animal within herd and determining prevalence of infection
  

How to prevent Antiparasitic Resistance

• Minimize drug use: Treat all susceptible animals at once. Treat all incoming animals prior to introduction. Treat at rational times. Allow pastures to remain empty over winter. Rotate pastures. Clean up poop
• Do not underdose: Underdosing facilitates survival of residual parasites and selection of resistant mutants. Surviving parasites get disseminated
• Rotate use of drugs with different mechanisms of action
• Using combo products with diff mechanisms of action vs. same type of parasites
  

Regulation of Antiparasitics

• Regulated by the EPA
• Extra-label drug use BANNED

Examples of Organophosphate/carbamate

• Cythionate
• Dichlorvos
• Fenthion
• diazinon
• trichlorphon
• coumaphos
• carbaryl
• Common products: Tiguvon, Spotton, Task Tabs, Pro-Spot, Proban. Plus sprays/shampoos, collars, powders

Examples of Pyrethrins/Pyrethroids

• Permethrin:
• pyrethroid  in combo with imidacloprid (K9 Advantix)
• pyrethroid in combo with pyriproxyfen (BioSpot for dogs)
• Deltamethrin: pyrethroid in collars for dogs

Mechanism of Organophosphates/Carbamates Action

• Neurotoxic
• Gets to parasite via ingestion/contact
  
• Induces parelysis by phosphorylating AChE within NMJ
• Paralysis due to overstimulation with excess ACh
• Must be administered freq because war off the animal quickly and degrade into inert metabolites
• Absorbed through skin and can cause dose-dependent adverse effects due to cross-reactivity with mammalian AChE

Mechanism of Permethrin/Pyrethroid Action

• Absorbed through the skin. Can have dose dependent adverse systemic effects via cross-reactivity with mammalian GABA-gated chloride receptors.
• Remain on animal for prolonged period of time
• Gets to parasite via ingestion and contact
• Induce paralysis by blocking GABA-gated chloride receptors within inhibitory interneurons

Spectrum of Activity for Organophosphates/carbamates

& Pyrethrins/Pyrethroids

• Insects: lice, feas, grubs, flies, mosquitoes
• Arachnids: Ticks, mites
• Also some activity vs. ascarids and cestodes (but due to resistance and inability to safely achieve high levels in GIT, not widely used for anthelmintic activity)

Uses for Organophosphates/carbamates & Pyrethrins/pyrethroids

• Insecticides in agriculture (plants, animals)
• Extermination of infested premises
• OTC flea and tick control
• Topically for prevention/treatment of fly, mosquito, flea, ked, tick, mite, and louse attack/infestation
• Exhibit repellent activity

Adverse reactions to Organophosphates/carbamates & pyrethrins/pyrethroids

• Dose dependent toxicity due to cross-reaction with mammalian AChE and GABA receptor (seizures, vomiting, tremors, bradycardia, ataxia, mm weakness, respiratory distress, hyperexcitability, salivation, diarrhea, bloat (ruminants), i.e. SLUDD
• DO NOT USE in cats.
• Organophosphate/carbamate toxicity reversed via atropine or pralidoxime (2-PAM). No antidote for pyrethrin/pyrethroids
• Toxicity is additive, and occurs when multiple products or multiple applications of products are used

Definition: Endectocides

Effective vs. both internal and external parasites

Organophosphates and Carbamates are bacteri_______

Pyrethrins and Pyrethroids are bacteri______

1. Cidal
2. Static

Examples of Macrocyclic Lactones

• Brand names: Ivomec, Heartguard, Revolution, Proheart, etc...
• Ivermectin, milbemycin, moxidectin, selamectin (long t1/2 - monthly or quarterly admin)

Mechanism of macrocyclic lactone action

• Ingested during blood meal
• Induce flaccid paralysis and death by blocking neurotransmission
• Enhance release of GABA at pre-synaptic neurosn within nematodes and arthropods
• GABA binds glutamate-gated chloride channel receptors in nematode and arthropod nerve and mm cells --> influx of chloride ions --> cell no longer receptive to deporalization

Spectrum of macrocyclic lactone

• Effective against:
• Insects: fleas, lice, bots, grubs, keds, mosquitoes, flies
• Arachnids: Ticks, mites
• Nematodes (roundworms) including Dirofilaria immitis microfilaria
• NOT effective vs. trematodes and cestodes

Use of Macrocyclic Lactones

• Endectocides (effective vs. both internal and external parasites)
• Used for control of arthropods and nematodes in both food and companion animals. As well as horticultural insecticide and for control of house pests like carpenter ants
• Systemically absorbed following oral, topical, and parenteral admin, except for brain.
  
• Horses: PO (effective for both internal and external parasites)
  
• Ruminants: PO, parenterally, or topically (effective for both internal and external parasites)
  
• Dogs/cats: PO or topically (PO dose effective for internal nematodes, but not enough for external arthropods. Topical use for external arthropod infestations)
• Can be used in combo with other arthropod control products.
  

Adverse Effects of Macrocyclic Lactones

• Serious adverse effects rare, but include:
• Fatal CNS depression in Collies: dose-related, and due to deficiency in P-glycoprotein which normally pumps macrocyclic lactone from CNS --> mm weakness, blindness, ataxia, paralysis, coma, and death. No antidote.
  
• Anaphylaxis of dogs with pre-existing heartworm infection due to Ags released by dying microfilaria
• Paralysis, staggering, bloat in cattle treated for grub infection due to death of larvae in vital areas
• Death of fish, amphibians, and insects via environ exposure as a result of excretion in urine and feces by treated animals.
  
• Safe for use with other antiparasitic drugs (clorsulon, nitenpyram, imidacloprid, fipronil, lufenuron, and methoprene). But should not be used with other macrocyclic-lactone containing products.
  

Brand name for Nitenpyram

Capstar

Mechanism of Nitenpyram action

• Following PO admin, rapidly absorbed and distributed in blood and excreted unchanged in urine with short t 1/2
• Adult fleas ingest drug during blood meal. Diffuses into flea and irreversibly binds nAChR --> paralyzed flea that dies due to constant depolarization
  

Spectrum of activity for Nitenpyram

Only for ADULT FLEAS. Must be administered daily for prolonged efficacy (non-residual).

Use of Nitenpyram

• Kills adult fleas in dogs and cats immediately
• Must be admin PO daily for prolonged effects

Side Effects of Nitenpyram

• Excreted rapidly, remains unchanged, and is highly specific for insect nAChR, virtually no adverse effects

Can be safely used in conjunction with other antiparasitic products including macrocyclic lactones, fipronil, lufenuron, and methoprene

Examples of Imidacloprid

• Advantage = imidacloprid only (does adult and larval fleas for dogs and cats)
• K9 Advantix = imidacloprid + permethrin. Permethrin repels mosquitoes, flies, tixcks, and has -cidal activity vs. ticks. NOT FOR CATS.
• Advantage Multi/Advocate = imidacloprid + moxidectin (macrocyclic lactone that confers activity vs ascarids, hookworms, whipwroms, and heartworm, ticks, mite, and lice). Used for both dogs and cats
• Systemic horticultural pesticide and for residential pest control
  

Mechanism of Imidacloprid Action

• Administered topically but not absorbed through host skin. Instead, re-distributes to hair follicoles and/or sebacious glands from which it is slowly released.
• Adult fleas exposed via contact with skin/hair of host
• Larval fleas exposed via ingestion/contact with sloughed skin cells
• Upon contact, diffuses into flea and irreversibly binds nAChR --> paralysis due to constant depolarization --> Death.

Spectrum of Imidacloprid Activity

• Effective against: insects including fleas (adult and larval stages only)
• NOT effective against: Flea eggs, ticks, mites, helminths

Adverse Effects of Imidacloprid:

• Horticultural and residential use of concern: colony collapse disorder in honey bees and very toxic to earthworms
• Since not absorbed systemically through skin AND highly specific for insect nAChR, few if any adverse effects.
• Excessive salivation due to bitter taste
• Safe to use with other antiparasitics (macrocyclic lactones, fipronil, lufenuron, and methoprene)

Brand names for Spinosyns

• Comfortis: spinosad alone PO for activity vs. adult fleas and nematodes
• Trifexis: spinosad + milbemycin (macrocyclic lactone) PO for activity vs adult fleas, ticks, and nematodes
• Assurity: spinetoram alone topically for activity against adult fleas only.

**All monthly application for residual arthropod +/- nematode control**

Mechanism of Spinosyn Action

• During blood meal, adult fleas ingest spinosad in blood or contact spinetoram present within oils of skin. Drugs irreversibly bind nAChR --> paralysis and death of adult fleas due to constant depolarization
• Spinetoram administered topically but not absorbed through skin of host. Redistributes to hair follicoles and/or sebaceous glands from which it is slowly released.
• Spinosad admin orally.
  

Spectrum of Activity

• Effective against Insects (including fleas) - adults and larval stages only
• NOT effective against flea eggs, ticks, mites, helminths

Adverse effects of Spinosyns

• Adverse effects observed with comfortis when used in combo with ivermectin (high dose), which results in ivermectin-related toxicities
• Excessive salivation when licked because of bitter taste

Examples of Fipronil

• Frontline Top Spot, EasySpot, and Parastar contain fipronil alone for activity vs. adult fleas and ticks. (also exhibits efficacy vs. mites and lice, but only Easyspot and Parastar labeled for it). Both dogs and cats
• Frontline Plus: fipronil + methoprene (insect growth inhibitor which confers additional activity vs. flea eggs and larvae). Both dogs and cats.
• All monthly admin.

Mechanism of Fipronil action

• Topical admin --> redistributes throught surface of body within 24 hrs. Lipophilicity of fipronil facilitates collectio nin oils on skin and hair follicles
• During blood meal, ticks, fleas, mites, and chewing lice contact fipronil within oils on skin and hair. Drug then diffuses into parasites and interferes with conduction of chloride ions in GABA- and glutamate-gated chloride channels. Results in paralysis of affected tick, flea, louse, or mite

Spectrum of Fipronil Activity

• Effective against: Fleas (adults only), ticks, mites, chewing lice
• NOT effective against: Flea eggs or larvae or helminths

Adverse Effects of Fipronil

• Applied topically and not absorbed systemically, few if any adverse effects observed. Mammals have very few GABA-gated Cl- channels
• Most common is skin irritation at site of application (hypersensitivity).
• Safe to use with other antiparasitic drugs, including macrocyclic lactones, nitenpyram, imidacloprid, lufenuron, and methoprene.

Examples of Metaflumizone

• Promeris for cats: metaflumazone alone for activity vs. adult fleas only (only for cats)
• Promeris for Dogs and Promeris Duo: metaflumazone plus amitraz (confers additional activity against ticks and mites). Only for dogs

**Both topical montly for residual arthropod control**

Mechanism of Metaflumizone action

• Topically administered, distributed throughout surface of body within 24 hrs. Lipophilicity faciliatates collection in the oils presen ton the skin and in hair follicles and slow prolonged release
• During blood meal, fleas contact drug within oils of skin and hair. Drug interferes with conduction of sodium ions along pre- and post- synaptic neurons --> paralysis and death of flea

Adverse Effects of Metaflumizone

• Topically applied and not absorbed systemically, few if any adverse effects observed.
• Accidental ingestion reportedly causes immediate salivation and head shaking. Smells bad too.

Three types of Insect growth inhibitors

Lufenuron

Pyriproxyfen

Methoprene

Brand names for Lufenuron products

• Program: lufenuron alone for activity vs flea eggs and larvae. For both dogs and cats
• Sentinel: lufenuron + milbemycin, a macrocyclic lactone which confers additional activity vs nematodes (ascarids, hookworms, whipworms, heartworms). Milbemycin also confers activity against ticks, mites, and lice but not labeled for htat. For both dogs and cats.
• Both are admin orally or parentally (cats) on monthly basis. Due to non-topical route, residue not present on pet surface.
• Can be used in combo with other arthropod control products.

Mechanism of Lufenuron Action

• Following absorption, accumulates in adipose tissue and slowly released back into circulation. Excreted unchanged in feces.
• Inhibits chitin formation by inducing disintegration of the epidermal cells responsible for chitin production (important b/c dep on dev stage of flea, 25-50% dry weight is chitin)
• Lufenuron specific for egg/larval stages because this is when chitin is formed
• Ingested by adult fleas during blood meal. Drug is passed into flea eggs via ovary. --> Eggs dessicate due to disruption of shell integrity (drug affects dev of chitin shell coating eggs). Larvae are also unable to hatch because they cannot cut through chitin eggshell, because drug affects dev of egg tooth
• Larve that hatch ingest lufenuron present in feces of adult fleas. Drug interferes with molting, so they die during their first molt.

Mechanism of Pyriproxyfen and methoprene Action

 Not known, but probably similar to lufenuron (chitin formation probs)

Brand names of products that contain pyriproxyfen

• BioSpot for Cats: pyriproxyfen alone for activity vs flea eggs and larvae.
• BioSpot for Dogs: pyriproxyfen + permethrin (pyrethroid which fxns as repellent for mosquitoes and ticks and has -cidal activity vs. ticks)

**Admin topically on monthly basis for residual flea plus/minus tick and mosquito control**

Brand names of products wtih Methoprene

• Frontline Plus: fipronil + methoprene.

Adverse effects of Lufenuron

• Activity highly specific for chitin, which is not mammalian, few if any adverswe effects associated with lufenuron admin
• Can be safely used in combo with other antiparasitic drugs, including macrocyclic lactones, fipronil, nitenpyram, and imidacloprid

Spectrum of Activity for Growth Inhibitors

• Effective against insects, including fleas: eggs and unhatched/hatched larval stages
• NOT effective against adult fleas, ticks, mites, or helminths.

Mechanism of Piperazine Activity

• Administered orally and systemically absorbed
• Functions either as GABA agonist at presynaptic neurons, or as a competitive antagonist of ACh within NMJ --> MM unable to contract such that worm undergoes flaccid paralysis and loses its grip on the host
• Live worms expelled via GI peristalsis
  
• If worm not expelled while drug is active, recover and survive
• No effect on helminth eggs --> feces contains infective eggs
  

Mechanism of Levamisole Activity

• Administered orally or SQ and systemically absorbed (Oral for GI nematodes, SQ for Lungworms)
• Functions as cholinergic agonists, and bind nAChR at NMJs --> MM contract such that worm undergoes spastic paralysis and loses its grip on the host
• Live worms expelled via GI peristalsis
  
• If worm not expelled while drug is active, recover and survive
• No effect on helminth eggs --> feces contains infective eggs

Mechanism of Pyrantel/morantel Activity

• Administered orally.
• Pyrantel/morantel pamoate remains in GIT
• Pyrantel/morantel citrate/tartrate systemically absorbed
  
• Functions as cholinergic agonists, and bind nAChR at NMJs --> MM contract such that worm undergoes spastic paralysis and loses its grip on the host
• Live worms expelled via GI peristalsis
  
• If worm not expelled while drug is active, recover and survive
• No effect on helminth eggs --> feces contains infective eggs

Spectrum of Activity for Piperazine, Levamisole & Pyrantel Morantel

• Effective against Nematodes (roundworms)
• Ineffective against Cestodes and Trematodes

Use of Piperazine

• Orally for immediate, non-residual treatment of GI nematodes in companion and food animals

Use of Levamisole

• PO for GI nematodes
• SQ for lung worms

For immediate, non-residual treatment of nematode infections in companion and food animals

Use of Pyrantel/Morantel

• Orally for immediate, non-residual treatement of nematode infections in companion and food animals
• Pyrantel/morantel pamoate: remain in GIT, and only for GI nematode infections
• Pyrantel/morantel citrate/tartrate: systemically absorbed and for both GI nematode and lung worm infections

Adverse Effects of Piperazines, levamisole, and Pyrantel/Morantel

• Piperazines - vomiting diarrhea
• Levamisole, pyrantel/morantel - SLUDD due to cholinergic activity (additive effect, so do not use levamisole, pyrantel/morantel, pyrethrins/pyrethroids, or organophosphates/carbamates in combo)
• Death can occur as a result of asphyxiation secondary to resp collapse
• Atropine (ACh competitive inhibitor) and pralidoxime (restores activity of phosphorylated AChE) can reverse toxicity
• Horses particularly sensitive to cholinergic effects. Only use pyrantel pamoate, which is not absorbed systemically

Brand name of drug containing Emodepside

• Profender (for kitty cats). Contains emodepside plus isoquinolone, praziquantel.
• Emodepside provides activity vs. nematodes.
• Praziquantel provides activity against cestodes (and also trematodes, but not labeled for this use)

Spectrum of Emodepside Activity

• Effective against Nematodes (roundworms)
• NOT effective against trematodes or cestodes

Mechanism of Emodepside Activity

• Following topical admin, absorbed into blood. During blood meal, ingested by nematode within GI or lung tissue
• Emodepside binds latrophilin receptor on pre-synaptic neurons --> influx of Ca++ and DAG into neuron --> release of inhibitory neuropeptides --> inhibit mm contration --> flaccid paralysis and death of nematode

Adverse effects of Emodepside

• Very few adverse effects and can be used in combo with other anthelmintics.
• Does not have activity vs. eggs
• Can induce excess salivation and cause irritation at application site.

Brand names of Drugs wtih Clorsulon

• Curatrem: clorsulon alone - only against trematodes
• Ivomec-F: Clorsulon plus ivermectin (macrocyclic lactone). Does trematodes, nematodes, and arthropods.

Mechanism of Clorsulon Action

• After PO and SQ admin, Clorulon present in blood (75% in serum, 25% in RBC).
• Flukes ingest drug during blood meal and inhibits two enzymes necessary for glycolysis in flukes (3-phosphoglycerate kinase and phospholyceromutase)
• Flukes cannot do glycolysis and can't produce ATP --> dies of starvation
• Young flukes (<8 wks old) minimally affected because they eat liver cells which don't contain drug. Only affected as they grow older and migrate within liver and induce hemorrhage. Can kill young flukes by using 2x dose.

Use of Clorsulon

• PO or SQ for non-residual treatment of trematode infections including Fasciola hepatica and Fascioloides magna in ruminants and camelids
• No direct activity against eggs.
• Used especially in ruminants for fluke control

Adverse Effects of Clorsulon

• Activity specific for fluke enzymes, so few if any adverse effects occur in mammalian hosts
• Can be combined with other anthelmintics

Examples of Isoquinolones

• Praziquantel (Droncit): PO and parenteral admin --> absorbed systemically and acts on cestodes and trematodes within AND outside GIT
• Epsiprantel (Cestex): PO, remains within GIT, and only effectivs vs. cestodes and trematodes within GIT.

Mechanism of Isoquinolone Activity

• Absorb isoquinolones through tegument
• Exact mechanism unknown
• Believed to increase Ca++ permeability --> muscle contraction/paralysis such that worm releases hold on the host
• Damage integument --> digestion within host GIT (intact worm or segments rarely seen in host feces)
• No effect vs eggs.
• Single dose is effective

Adverse Effects of Isoquinolones

• Occasional vomiting, diarrhea, drowsiness, ataxia, and salivation
• Safe to combine with other anthelmintics

Examples of Benzamidazoles

Fenbendazole, albendazole, thiabendazole, etc...

Mechanism of Benzamidazole Activity

• Inhibit helminth-specific mitochondrial fumarate reductase such that parasite eventually becomes deprived of energy
• Irreversibly bind parasite B-tubulin, wuch that it cannot be polymerized into cytoplasmic microtubules
• This affects parasites because microtubules are essential for nutrient uptake by parasite intestinal cells --> cannot uptake glucose into cells --> glycogen stores become depleted and ATP no longer formed
• Malfunction of mitotic spindles which can result in chromosomal doubling in eggs.
• Worms AND egs expelled dead and usually whole via normal peristalsis
  

**Starvation takes a long time, so critical factor in benzamidazole efficacy is prolonged contact time between drug and parasite**

Resistance to benzamidazoles

Wide Spread

Adverse Effects and Pharmacokinetics of Benzamidazoles

• Poorly water-soluble: PO as suspensions, pastes, or powders
• Usually remain in GIT after PO admin.
• Albendazole (all species) and Fenbendazole (dogs/cats) absorbed in sufficient quantities to be active vs. systemic helminths (liver and lung flukes, lungworms)
• Most effective in horses and ruminants due to proonged transit time through GIT
• Very few toxic effects. Potentially teratogenic due to binding of microtubules. DO NOT GIVE to pregnant animals.

Spectrum of Activity of Benzamidazoles

• Effective against Nematodes, Cestodes, and Trematodes (both eggs and worms)

Use of Benzamidazoles

• PO for treatment and control of nematodes, cestodes, and trematodes in food and companion animals