Lecture 11 & 12: Anti-Parasitic Drugs

What are the three main types of antiparasitic drugs?

1. anthelmintics

2. antiprotozoals

3. ectoparasiticides

What are the major classes of anthelmintics?

• benzimidazoles

• macrocyclic lactones

• isoquinolones

• nicotinic paralytics

What are the major classes of antiprotozoals?

• ionophores

• sulfonamides

• triazines

• nitroimidazoles

What are the major classes of ectoparasiticides?

• pyrethrins/pyrethroids

• neonicotinoides

• isoxazolines

• IGRs

How do antiparasitic drugs work?

By targeting parasite-specific systems —nervous system, structure, or metabolism - minimizing harm to the host

What are the common MOAs of anthelmintics?

• Paralysis – (Spastic or Flaccid ) so parasites are expelled by peristalsis

• Disruption of parasite metabolism – Energy deprivation, starvation

What broad-spectrum anthelmintics are active against GI and lung nematodes, many cestodes, and some trematodes?

BZDs and pro-benzimidazoles

What are the key advantages of BZDs?

• High therapeutic index and minimal host toxicity.

• Multiple formulations: oral drench, paste, feed additive, bolus.

• Economical and safe for most species.

What BZDs have strong GI persistance?

BZD- methylcarbamates: albendazole, fenbendazole, mebendazole

How are BZDs administered?

orally as suspension, granules, feed blocks, or paste (equine)

What is the MOA of BZDs?

• Bind selectively to β-tubulin → inhibit microtubule polymerization

  in parasite cells.

• Disrupts cell division, glucose uptake, intracellular transport, and cytoskeletal integrity.

• Leads to energy depletion (↓ATP) → starvation → parasite death.

What explains the selective toxicity and wide safety margin of BZDs?

parasite beta-tubulin affinity »»» host

What is a possible negative side effect of BZDs?

reduced nutrient absorption

What factors influence BZD efficacy?

• Feed intake and GI transit time.

• Rumen bypass (esophageal groove closure in young animals).

• Liver disease or parasite metabolism (e.g., Fasciola oxidizes Albendazole).

• Parasite location and cuticle permeability.

What are the clinical uses of BZDs?

• Control of adult and larval nematodes, lungworms, and some tapeworms.

• Used across species: cattle, sheep, goats, horses, swine, dogs, cats, and poultry.

• Combined products often include Febantel + Praziquantel + Pyrantel (broad coverage).

When should BZDs not be used?

in early pregnancy - teratogenic risk

What antiparastic class is available in injectable, pour-on, and oral formulations and has activity against endoparasites (worms) and ectoparasites (fleas, ticks, etc) but no activity against cestodes?

macrocyclic lactones

What is the MOA of MLs?

• High affinity for Glutamate-gated Chloride channels (GluCls) unique to invertebrate species → Increased permeability to Cl ions → Hyperpolarization & flaccid paralysis of somatic musculature (can’t stay in place) → Paralytic effect on pharyngeal pump (can’t feed) → Inhibition of female reproductive output

• Stimulation (agonist) of GABA regulated chloride channels, muscular paralysis → Parasites that can’t feed are dead parasites

How do MLs offer long-acting protection?

reservoir effect in adipose tissue

Why do MLs have limitations in treating lung parasites?

• Poor diffusion into encapsulated or nodular lesions (e.g., Filaroides osleri).

• May suppress larval shedding but not eliminate infection.

• Bioavailability highly dependent on tissue perfusion and host body-fat content.

Why should MLs not be used in those with the MDR1 gene mutation?

Leads to neurotoxicity (ataxia, tremors, coma) even at standard doses of IVM, Doramectin.

What are some MLs approved for use in animals?

What cholinergic anthelmintics are commonly used in vet med?

• levamisole

• pyrantel

• morantel

What is the MOA of isoquonolones (praziquantel and epsiparental)?

• Increase in membrane permeability to Calcium ions → Sustained contractions → Spastic paralysis → Parasites loose grip and expelled out.

• Vacuolization of tegument → Interfere with nutrient absorption, Exposure of parasite antigen → Attack by host immune cells into the parasite

What cyclic depsipeptide is fully effective against ascarids and hookworms, but is only FDA-approved for use in cats?

emodepside (profender)

What is the unique MOA of emodepside?

What human side effect is of concern when applying emodepside?

pregnant women should avoid contact

What narrow spectrum anthelmintic is exclusively effective against ascarids (rounds)?

piperazine

What is the use of piperazine?

What is the MOA of piperazine?

GABA Agonist - Opening of CL-àHyperpolarizationàFlaccid ParalysisàExpulsion

What species is melarsomine dihydrochloride (arsenical) contraindicated in due to severe toxicity (also should never be administered SC or IV)?

cats

What are the key clinical considerations of melarsomine dihydrochloride (arsenical)?

• Strict rest is mandatory during and for weeks after treatment to minimize embolism risk.

• Administer macrocyclic lactones and doxycycline prior to melarsomine to reduce Wolbachia burden, improving efficacy and safety.

• The only approved adulticide for heartworm disease in dogs in the U.S.

Why is fenbendazole the drug of choice for giardia in cats and pregnant animals (extra-label use for dogs)?

poor absorption → high concentration in the GI lumen where giardia resides

Why is albendazole contraindicated in dogs and cats for routine giardiasis?

due to risk of idiosyncratic aplastic anemia and myelosuppression, also teratogenic

How do nitroimidazoles work?

• Enter parasite/bacterial cells by passive diffusion.

• Activated only in anaerobic conditions → enzymes (e.g., ferredoxin) convert drug to toxic free radicals.

• Free radicals damage DNA → strand breakage and cell death.

• Selective toxicity: Mammalian cells lack these anaerobic activation enzymes.

What are the clinical uses of nitroimidazole?

• Metronidazole: Giardia, Trichomonas, Entamoeba, anaerobic bacterial infections, adjunct for IBD (anti-inflammatory effect).

• Ronidazole: Tritrichomonas foetus infection in cats.

• Tinidazole: Same spectrum, sometimes used when metronidazole intolerance or resistance occurs

What toxicities and contraindications are associated with nitroimidazoles?

• Neurologic: Ataxia, nystagmus, seizures (dose-related).

• GI upset: Anorexia, vomiting

• 🚫 BANNED in food-producing animals – carcinogenic risk.

Nitroimidazoles are highly effective against anaerobes and protozoa, but _____ at high doses and strictly prohibited in livestock.

neurotoxic

How do folate inhibitors (sulfonamides) work?

• Sulfonamides block dihydropteroate synthase (DHPS); Trimethoprim/Pyrimethamine block dihydrofolate reductase (DHFR).

• Together cause a sequential blockade of folate synthesis, stopping DNA formation → cidal effect.

• Selective: Mammals use dietary folate, parasites must synthesize it.

What are the clinical uses of folate inhibitors?

• Sulfadimethoxine (Albon®): Coccidiosis (Cystoisospora) in dogs/cats.

• Trimethoprim-Sulfa (TMS): Broad protozoal & bacterial infections.

• Pyrimethamine + Sulfadiazine: Toxoplasmosis / Neosporosis (CNS).

What are the adverse effects of folate inhibitors?

• KCS (dry eye) in dogs, bone marrow suppression, and hypersensitivity (fever/polyarthritis).

• Less effective in purulent sites (excess PABA).

What is the MOA of Triazines (Toltrazuril/Diclazuril, Ponazuril)?

• Primary target is the apicoplast, a unique organelle in Apicomplexans.

• Disrupts essential metabolic pathways (e.g., fatty acid synthesis); Also interferes with mitochondrial electron transport.

• Cidal against all intracellular stages (asexual and sexual).

What is the FDA-approved choice for EPM (sarcocystis neurona) in horses?

ponazuril

What is the MOA of ionophores?

• Lipid-soluble molecules that form complexes with cations Na+/H+/K+/Ca2+

• Shuttle ions across cell membranes, collapsing electrochemical gradients.

• Leads to parasite cell swelling and lysis.

• In ruminants, also alters rumen flora to improve feed efficiency.

What are the clinical uses of ionophores?

• Prevention of coccidiosis (Eimeria) in poultry and ruminants.

• Growth promotion in cattle.

• NOT for treatment of clinical disease.

What is the main toxicity associated with ionophores?

cardiotoxicity in horses - often fatal

What is the MOA of isoxazolines?

Non-competitive antagonist of GABA & Glutamate-gated chloride channels → hyperexcitation & paralysis of ectoparasites

What drug has ultra-rapid onset - killing adult fleas before egg laying, helping environmental control?

neonicotinoids

What are the clinical uses of pyrethrins and pyrethroids (sodium channel modulators)?

• Topical applications: sprays, spot-ons, shampoos, collars

• Broad spectrum: fleas, ticks, mosquitoes, flies, lice

• Dogs: K9 Advantix® (Permethrin)

• Cats: Seresto® collar (Flumethrin - CAT-SAFE pyrethroid)

What species is permethrin extremely toxic to?

cats

What is the primary drug used for generalized demodicosis in dogs and can also be used for tick prevention?

Amitraz

What is the primary drug used for sarcoptic mange in dogs?

benzoyl benzoate

What are the MOAs of insect growth regulators?

• Juvenile Hormone Analogs (JHAs): Mimic insect juvenile hormone → prevent maturation to adults

• Chitin Synthesis Inhibitors (CSIs): Disrupt molting and egg hatching by inhibiting chitin formation

What are the clinical applications of IGRs?

• Must be combined with an adulticide for complete flea control

• Essential for breaking flea life cycle and controlling environmental infestations

• Extremely safe for mammals (no juvenile hormones or chitin in hosts)

What is the difference between carbamates and organophosphates?

• Both classes inhibit acetylcholinesterase (AChE) → acetylcholine accumulation → continuous nerve stimulation

• Key Difference: OPs form irreversible bonds; Carbamates form reversible bonds