AntiParasitic drugs Flashcards
5 characteristics of the ideal parasiticide?
• selective toxicity
• economical to purchase
& apply
(small vs. large animal)
- hits all stages of parasite development disrupting the entire life cycle
- safe for use in “at risk” animals
- does NOT induce resistance in the parasite** no such thing!
Food animal production
vs
small animal/equine medical care
• Economics of anti parasitic
- food animal production
- -> economic return on entire herd health
- pets & horses
= control of zoonotic disease & health of individual pet
4 categories of “at risk” patients (concerning anti-parasitics)?
- old
- young
- pregnant
- debilitated
Why is it difficult to prove the presence of parasite resistance in animals?
- Hard to separate out drug administration errors vs actual drug failure
- Can’t culture them
How does selective pressure result in emergence of resistant populations?
- allows resistance to emerge by killing all susceptible & allowing resistant forms to remain
What is refugia?
How does it ↓ the # of resistant organisms in a population?
Does refugia try to reduce resistant organisms to zero?
Refugia
- a portion of a population of parasites that survives or avoids exposure to an antiparasitic drug treatment
- subset population of population is NOT subjected to drug
- -> allows susceptible parasites to compete w/ resistant forms
- -> keeps resistant forms low
- -> slows resistance development w/ low worm burden present
5 methods to reduce development of parasite resistance to antiparasiticides?
• Refugia = good management practice
• Use only drugs known to be effective against
the target species of parasite
• Target only health threatening parasite
species; reduce population to safe level
• Drugs that work by different mechanisms
- if combine drug
• Rotate type of drugs used over time (equine)
EPA vs. FDA
• regulatory fxns?
• What drugs or compounds would fall under each?
How does this translate to availability as OTC products?
EPA
• controls pesticides
• available OTC
• applied topically
FDA
• regulates internal drugs
• Legend drugs
legend drugs
• what are they?
• who regulates them?
- given internally (PO or by injection)
- prescription only
- on or by order of vet
- must have valid VCPR
- FDA regulated
ectoparasiticides
-External antiparasitics
endoparasiticides
-Internal antiparasitics
endectocides
-Compounds that do both internal and external parasites
Term that describes drugs against any internal worm parasite
-anthelmintics
Term used to describe drug against roundworms
Vermicide VS Vermifuge?
-antinematodals
Vermicide
• Kills
Vermifuge
• paralyzes –> expulsion
Term used to describe drug against tapeworms
• what are the specific types?
-anticestodals
Cestocides
Taeniacides
Taeniafuge
Term used to describe drug against Flukes
-antitrematodals
2 groups of macrolides or macrocyclic lactones?
members of each of these groups?
1 - Avermectins
• Ivermectin
• Selamectin
• Doramectin
• Eprinomectin
2- Milbemycins
• Milbemycin oxime
• Moxidectin
Are avermectins & milbemycins lipophilic or hydrophilic type drugs?
How does this translate to the ability of the drug to reach many target sites?
- Lipophilic
Wide distribution
• GI mucosa
• Lungs
• Dermis
** able to target migrating larvae
what receptor do macrocyclic lactones work on?
• MOA?
How does this actually kill the parasite?
Bind to glutamate receptor sites on chloride channels
- -> open channel
- -> Cl- enters cells
- -> ↑ threshold
- -> pharyngeal muscle paralysis
- -> starve & can’t hold on
- -> flushed out
Why are macrolides NOT effective against cestodes & trematodes?
- Flukes & Tapes do NOT have glutamate receptors
= not susceptible
Mammalian receptor macrocyclic lactones combine with to produce toxicity?
- Why are these still safe drugs for most animals?
- Mammals don’t have PERIPHERAL glutamate receptors
• Cl- gated GABA receptors in CNS
- macrolides can activate - BBB protects most
What keeps Macrocyclic Lactones out of the brain?
- P-glycoprotein
P-glycoprotein
- Cell membrane pump
- -> transports selected drugs from INTRA to Extracellular
Where is P-gp found
- endothelial cells of BBB
- GI epithelial cells
- bile canaliculi
- renal PCT
What gene produces P-glycoprotein?
2 names
- MDR1 gene
(multiple drug resistant) - ABCB1 gene
“ATP-binding cassette transporters” (ABC)
Why can macrocyclic lactones kill parasites for such a long period of time w/o using high dosages of drug?
1ng of drug/g of tissue
• Persistence of drug in target tissue
+ low drug concentration needed to kill parasite
–> 1 dose per month possible
• Enterohepatic circulation
Why are avermectins & milbemycin more effective at killing mites, ticks, and sucking lice,
- but less effective at killing biting lice?
• concentrations in skin sufficient to kill mites, sucking lice, and ticks
(but not superficially-feeding biting lice)
How are macrolides primarily excreted from the body?
- intact by the liver into the feces (biliary excretion)
Why is it that once a macrolide is excreted from the body, it can then re-enter the body?
What is the this process called?
impact on the duration of action?
- Because they are lipophilic
- -> reabsorption
enterohepatic circulation
explains long lasting effect of these drugs
Why does the persistence of avermectins & milbemycin in the body have an economic impact on their use in livestock?
pour-on vs injectable w/drawl time?
- stay in tissues for a long time!
• 1% injectable = 35-50d
• 3.15% = 120d
Pour ons
• no withdraw
Why are there no injectable macrocyclic lactones approved for use in dairy cattle?
• whats used instead?
- MLs are heavily excreted in the milk if absorbed into the blood
BUT pour ons forms are approved for dairy because of topical route and poor absorption into body
• eprinomectin (Eprinex®)
• moxidectin (Cydectin®)
What genetic mutation results in production of poorly functioning P-glycoprotein molecules?
In what breeds is this common?
Mechanism –> ↑ susceptibility to adverse effects from drugs like ivermectin?
What does the avermectin/milbemycin molecule do to mammalian brain cells?
Homologous mutation of the MDR1 gene
- Collies
- some Shetland sheepdogs
- Australian shepherds
• ↑ GI tract absorption • ↓ liver elimination --> ↑ drug enters CNS --> reaches the mammalian GABA receptors --> opening Cl- gate --> hyperpolariz.
What drugs can produce a collie-like susceptibility in animals that usually would not be sensitive to avermectins?
• why?
- ketoconazole (anti fungal)
- itraconazole (anti fungal)
- phenothiazine tranquilizers
• inhibits P-gp
impairs ability of P-gp to exclude macrocyclics from CNS!greater amounts avermectins and milbemycin enter CNS
How do dogs typically become intoxicated with horse avermectins?
- chew on equine paste syringe
- LA injectable used on dog/cat
- -> high dose
- -> overwhelming p-gp’s in CNS
- -> toxicosis
Clinical signs in dogs with avermectin toxicosis?
Tx of avermectin toxicosis? Is there an antidote?
How long can toxicosis last? Why do they last this long?
Clinical signs • CNS depression • Vomiting • salivation early • Ataxia, stupor, coma, mydriasis, blindness
Tx
• supportive
Lasts DAYS to WEEKS due to adipose & enterohepatocirculation
The presence of resistance of heartworm parasites to avermectins is controversial.
Why is this a difficult issue to resolve one way or the other as to whether real resistance to avermectins used in the field exists?
-
??
What was the first avermectin approved for use in dogs?
-Ivermectin
How does the dose at which collies die from ivermectin toxicosis compare to the dose given in preventative drugs like Heartgard?
Is ivermectin safe in cats?
manufacturer recommends observing for 8 hrs after heartworm prevention
Collie death – 0.2 mg/kg
• normal dose = 0.006 mg/kg
Cats are NOT especially sensitive to ivermectin
Which avermectin heartworm preventative is only TOPICALLY applied, is approved for dogs and cats,
- also approved for control of fleas, ear mites, sarcoptic mange and ticks?
-Selamectin (Revolution®)
What are the 2 large animal avermectin drugs?
- Doramectin (Dectomax®)
• injectable and pour on
- Eprinomectin (Eprinex®)
• topical (pour on)
internal worms,
grubs,
lice,
mange mitesWhat are the 2 milbemycin type drugs used in veterinary medicine?
???
- Milbemycin oxime
* Moxidectin
Which milbemycin type compound is FDA approved for use in small animals for:
- monthly heartworm preventative,
- control of roundworms (ascarids),
- hookworms,
- and whipworms?
Sentinel® - with lufenuron
Trifexis® - with spinosad
** extra lable for deomdectic mange
Which milbemycin type compound is FDA approved for use in cattle & horses to tx:
- mites,
- grubs,
- horse stomach bots,
- lice,
- flies?
-Moxidectin
• Cattle
- Cydectin® drench
• Horse
- Quest® = OTC drug
Which macrolide is approved as a 6-MONTH INJECTABLE HEARTWORM PREVENTATIVE in dogs only?
-Moxidectin
= ProHeart 6
Which group of antinematodals works by inhibiting the formation of the cell’s cytoskeleton?
What component of the cytoskeleton is disrupted?
Why are these drugs so safe for use in mammals?
- Benzimidazoles
β-tubulin
• (w/ α-tubulin ) forms cell microtubules of cell’s cytoskeleton
benzimidazoles DON’T COMBINE with mammalian B-tubulin = Safe
What is the prototype drug of the benzimidazoles?
Besides the antinematodal effect, what other “anti” effect does it have?
- thiabendazole
• Also has anti-fungal effect
therefore added to otic drops!
What is one of the common uses of thiabendazole?
- otic drops
What parasite produces hydatid cysts in the liver of humans?
Ecchynicoccus multilocularis
Which benzimidazole is: - approved for use in dogs & livestock as an antinematoda
- effective against taenia species of tapeworms
- NOT effective against Echinococcus species
- has to be given 3 consecutive doses in a row (once daily) to be effective?
-Fenbendazole
Which benzimidazole is ONLY approved for EQUINE use, is given only by the oral route, and is effective against common equine nematodes
-Oxibendazole (Anthelcide EQ®)
What is the benzimidazole that is:
- a pro-drug
- is approved for canine use
- incorporated w/ anticestodal drugs & pyrantel in other products.
- Febantel (Drontal Plus®)
—> converted to fenbendazole & oxfendazole by the body
What is the very safe OTC antinematodal drug that:
- has limited spectrum of activity only against roundworms (ascarids) and hookworms,
- NOT whipworms or cestodes,
- comes in 2 FORMS, one water soluble & the other very insoluble (suspension).
- Pyrantel
• pyrantel pamoate (suspension)
- vigorously shaken before withdrawing oral dose
• pyrantel tartrate (water soluble)
pyrantel
• MOA?
Why does the parasite initially show nervous system stimulation followed by paralysis?
- nicotinic Ach receptors & excessively stimulates them
- -> initial depolarization
- -> NOT repolarizing
- -> Spastic paralysis
What are the active ingredients in Heartgard Plus?
- ivermectin + pyrantel
What are the active ingredients in Drontal Plus?
- praziquantel + febantel + pyrantel
Which 30 day,
single dose,
topically applied antinematodal works by: ↑ing intracellular Ca influx – what does it result in?
-Emodepside
• combined w/ praziquantel = Profender®
- -> vesicles containing an inhibitory NT being released
- -> flaccid paralysis of the parasite muscles
What precautions should the owner know about emodepside & aquariums or fish ponds?
- VERY Toxic to fish!
• they don’t have p-gp to exclude from entering CNS
What OTC antinematodal is:
- effective ONLY against roundworms (ascarids),
- not hookworms, whipworms, or cestodes.
Is this drug a vermicide or vermifuge?
-Piperazine
• vermifuge --> stimulates GABA receptor --> Cl- channel --> hyperpolarization --> flaccid paralysis = expulsion of roundworms
If a blood transfusion is given from a heartworm positive dog with microfilaria in the blood to a heartworm negative dog, would the transfer of microfilaria result in the blood recipient developing heartworm disease? Why or why not?
No, microfilaria aren’t the infective stage.
L3 from the mosquito is infective.
What is the rickettsial organism that has a symbionic relationship with Dirofilaria immitis?
Wolbachia
– ovarian inhabitant
Is heartworm disease more likely produce pulmonary edema or abdominal ascites?
- ??
