23 – Parasiticides I Flashcards
Basic principles of parasiticides
- Need to have a good idea of what you are treating
o Life cycle
o Parts of life cycle that can’t be treated - Need to know duration of treatment if you want to eradicate
- *management
Benzimidazole mechanism of action
- Binds to parasite beta-tubulin subunit (microtubule)
o Disrupts parasite cell shape, division, motility, secretion, absorption, etc.
o Binds to mammalian tubulin too, but dissociates quickly=little effect - *increase drug-parasite exposure time correlates with efficacy
- (microtubule disruptors in chemo drugs)
Benzimidazole generally safe in mammals: one example in dogs with prolonged dosing in dogs
- Bone marrow hypoplasia and pancytopenia reported after PROLONGED DOSING in puppies at high doses
- *generally not many side effects
Benzimidazole spectrum of activity
- BROAD SPECTRUM ANTIHELMINTICS
o GI and lung nematodes (roundworms)
o Some cestodes (tapeworms) and trematodes (flukes: minimal as in liver and not much exposure happens there)
Differences in anthelmintic activity between benzimidazoles is likely due to differences in
- PK (ie. Absorption and distribution)
- *anthelmintic potency generally similar
Benzimidazole PK: absorption
- Generally poorly water-soluble
o Formulations: pastes, suspensions, granules - Usually poor ORAL bioavailability
o Limited by solubility in GI tract (fine for GI roundworm efficacy)
o Works well in ruminants: rumen is a reservoir and then slowly released into intestines
Benzimidazole PK: distribution
- Generally high (but variable)
Benzimidazole PK: metabolism and excretion
- Extensive HEPATIC metabolism (CYP enzymes)
o 1st pass effects if oral absorption does occur - Also metabolism in lungs and intestines
- *metabolites have varying levels of activity
What are some benzimidazole formulations?
- *Fenbendazole (ex. Panacur, Safe-Guard)
- Febental
- Albendazole
- (NOT in Canada: Triclabendazole)
Fenbendazole is licensed for use in
- Horses (suspensions, pastes, granules)
- Cattle (suspensions, feed premixes)
- Swine, chicken, turkeys (Gel or Safe-guard mix)
- Dogs (panacur granules)
What are the label claims of Fenbendazole?
- Wide range of NEMATODES (especially adult GI worms, lung worms)
o Strongyles, ascarids, whipworms, hookworms, pinworms, etc.
o Cestodes: Taenia claim in DOGS
Fenbendazole is commonly used OFF-LABEL in
- Small ruminants (sheep and goats)
- Cats
- birds/reptiles/other exotics
- *can be used as it has a DIN
Fenbendazole off-label use in cats
- used for variety of nematode infections, Giardia
- popular choice for clinical disease associated with lungworm (Aelurostrongylus)
Febental
- fenbendazole pro-drug
Drontal plus:
- Febental, includes pyrantel (just another general dewormer) and praziquantel (specific for tapeworms)
- licensed for use in dogs
- *’general dewormer’
Albendazole (Valbazen)
- oral suspension licensed for use in cattle
- *do get into the blood stream (likely why some fluke activity)
- possible teratogenic early in gestation (don’t use within 21 days of breeding)
Albendazole (Valbazen) indications
- some ADULT flukes (Fasciola hepatica)
- ADULT tapeworms
- Same GI and lung adult round worms as Fenbendazole
Triclabendazole (Fascinex)
- Like albendazole with Cl- attached
- Active against adult and JUVENILE F. hepatica
- Active against F. gigantica, F. magna and Paragonimus (lung fluke)
- *gets flukes super well but not other things (gets all stages!)
- NOT licensed in Canada
o Emergency drug release
What is an emergency drug release?
- Authorization to permit the manufacture of a new drug to sell a limited quantity of new drug to veterinarian
o Not marketed in Canada
o Requested by practitioner for purpose of diagnosing or treating a medical emergency
What are the foreign drug eligibility criteria for an emergency drug release?
- Medication used to treat/diagnose and SERIOUS disease condition
- NOT marketed in Canada
- Documented clinical efficacy and target animal safety data are available for product
- No comparable products available for effectively diagnosing/treating the condition
What products are NOT eligible for an emergency drug release?
- Biologics are not approved by Health Canada
- Investigational drugs that are not approved in other jurisdictions
- Products where a comparable product is currently marked in Canada
o Cost and ease of use are NOT consider valid reason for requesting EDR - *not meant for a way for a company to circumvent the vet drug approval process
Macrocyclic lactones
- Related to macrolide antibiotics
- Produced by fermentation by Streptomyces in soil
- Considered endectocides
o Kill BOTH internal and external parasites
What are the 2 macrocyclic lactone groups?
- Avermectins
- Milbemycins
What are examples of Avermectins?
- Ivermectin
- Selamectin
- Eprinomectin
- (Doramectin)
- (Abamectin)
What are examples of Mibemycins
- Moxidectin
- Milbemycin
Macrocyclic lactone mechanism of action
- *Activates (opens) glutamate-gated Cl- channel
- Cl- entry into cell (hyperpolarization)
- Flaccid paralysis in worm
o Pharyngeal muscles: can’t ingest nutrients
o Somatic muscles: can’t move - May bind with GABA receptors at high concentration
- *NEUROTOXIN ON PARASITES
Macrocyclic lactones are effective against
- Nematodes and arthropods
o Exceptions: demodex mites, some ADULT filaria (heart worm) less susceptible
o Heartworm prevention dose is very low (1-10% of typical dose) - *differences in activity and potency between them
Macrocyclic lactones spectrum of activity
- Effective against most nematodes and arthropods
- Minimal activity against cestodes and trematodes
- Oral or transcuticular absorption of ML by parasite from the treated host animal
Macrocyclic Lactone PK
- Oral, topical or injectable products
o Topical can be oral too=transfer by grooming (ex. cows) - Generally lipophilic: high volume of distribution (especially MOXIDECTIN!)
- Some hepatic metabolism, mostly excreted via bile/feces
- Elimination half-life 1-3 weeks
Macrocyclic lactone elimination half life: 1-3 weeks
- Watch withdrawal times: typically very long
- *Milk: not licensed for diary cows (except moxidectin and one formulation of eprinomectin)
What are the adverse events of macrocyclic lactones?
- Generally safe, but when AE do occur=more significant then benzimidazoles
- Toxicity: associated with GABA stimulation in CNS
o Treatment=supportive care (fluids, oxygen, etc) (IV lipid emulsion?) - Normally little distribution to CNS, but exceptions
Exceptions of macrocyclic lactones that have more distribution to the CNS
- ABC-B1 mutant dogs (‘white feed, don’t treat’)
- Decrease P-gp function=increase distribution into brain
Ivermectin (Ivomec=pioneer drugs, but many generics available) ‘solutions’
- Oral drench: sheep
- Oral paste: horse
- Injectable: cattle, sheep, swine
- Oral premix: swine
- Oral tablet: dogs (*heartworm prevention with pyrantel)
- *withdrawal for meat and MILK (long time)
- *good for round worms, no activities on tape worms
Eqvalan gold paste
- Ivermectin
- With praziquantel: for tapeworms
- *be skeptical of drug marketing (duration?)
Heartgard
- First prevention for heart worm
- Very LOW ivermectin content for heart worm prevention
- Pyrantel: more of the dewormer
Eprinex Pour On (Eprinomectin)
- Similar compound to Ivermectin
- Licensed for use in dairy cattle with NO MILK WITHOLDING TIME
o Has Maximum Residue Limit (MRL) in milk
o Unlike ivermectin (no MRL for milk in Canada) - *not licensed for GOATS
Ivomec and Eprinex by same company
- Look similar
- *need to clarify=if wrong product=dump milk for 2 months!
Long range (Eprinomectin)
- Extended released SC injection
- 2 different solvent carriers: rapid and slow absorption
- 4-5 month activity against some worms
- 4 month meat withdrawal period
- *NOT FOR USE IN DAIRY COWS
Revolution (Selamectin)
- Monthly topical formulation for cats and dogs (SMALL ANIMAL)
- *Less affinity for P-gp than ivermectin
o Safer for ABC-B1 mutants: not necessarily ‘safe’ - Interest for use in aquaculture: fee premix for control of sea lice in salmonids
What are some uses of revolution (selamectin)?
- Fleas
- (Ticks: efficacy is limited, still bitten)
- Mites
- Nematodes (hook and round worms)
- HEARTWORM PRVENTION
- *topical and gets into systemic circulation
Moxidectin ‘types available’
- Quest/Quest Plus oral gel: horses
- Advantage multi (monthly topical: dogs, cats, ferrets)
- ProHeart 6 (sustained release injection)
- With various isooxazoline formulations
- *good for treating mange
Quest/Quest plus oral gel (horses)
- Moxidectin +/- praziquantel
- All kinds of nematodes +/- tapeworms
Advantage multi (monthly topical)
- Moxidectin + imidacloprid
- Heartworm prevention
- Fleas, ear mites, GI nematodes
ProHeart 6
- Heart work prevention for 6 months
Milbemycin in small animals: monthly tablets
- Milbemax tablets: cats
- Interceptor tables: dogs and cats
- Sentinel tablets: dogs
- Trifexis tablet: dogs
- Nexgard spectra: dogs
- *all get the same things
Milbemycin tablets treat/prevent
- Heartworm prevention
- Hookworm
- Round worm
- Tapeworm
- Whipworm
Macrocyclic lactone resistance
- Huge problem in sheep
- Emerging in cattle/horses
- *widely reported in cyasthostomes and small strongyles
- *ex. hemonchus
What are the resistance mechanisms?
- Induction of parasite efflux pumps (ex. P-gp)
- Changes in Glu-gated Cl- channels
How do you test for resistance parasites?
- Fecal egg count reduction
o Pre- and post- treatment fecal egg counts
o Resistance if not at least 95% reduction in counts
Macrocyclic lactones ecological impact
- Persist in feces for a long time
o Can kill insects that degrade feces (ex. dung beetle) - Evaluate as part of drug approval process
- *don’t dissolve out of feces (don’t need to worry about water contamination)
How might you change the PK properties to mitigate the potential risk of ecological impact of macrocyclic lactones?
- *excreted in different form or completely metabolized by liver
Macrocyclic lactones: topical tips
- Apply to SKIN: not hair
- Watch for skin/hair condition (ex. mud/feces)
- Decreased efficacy if applied at very low temperatures
- Flammable (watch out while branding!)