Antiparasitics Chapter 12-3 Dr. Dipa Brahmbhatt VMD MpH dbrahmbh@yahoo.com

Objectives Terminology – antiparasitics MOA antiparasitics Precautions of antiparisitics

Heartworm Prevention and Treatment

Treatment of Heartworm Disease Heartworm disease is caused by the filarial nematode Dirofilaria immitis Three stages of management of heartworm disease Adulticide therapy Microfilaricides: Eradication of circulating microfilariae after infection Preventing third-stage larvae from reaching maturity (preventative)

Treatment of Heartworm Disease Adulticide therapy Melarsomine - Immiticide® 1996 Given in the epaxial muscles BETWEEN L3 & L5 Arsenic compound Less toxic than former drug (Caparsolate® - thiacetarsamide) SE: include coughing, gagging, and lethargy, pulmonary congestion, localized inflammation: thromboembolism (fragments of worms) swelling and pain Nephrotoxicity and hepatotoxicity have been reported. Class 3: fatigue, dyspnea, right heart changes in radiograph, RHF : slow kill Class 4: Not recommended for animals with caval syndrome (large numbers of adult heartworms in the right ventricle, right atrium, and vena cava).

Heartworm Treatment – Slow Kill Method – VTI Team: Dr. B, Dr. Dev, Miss Kennar, Miss Foitnik Doxycycline: 5 – 10 mg/ kg (SID or BID) Prednisone: 1 mg/kg : BID X 7 days; SID X 7 days, EOD X 7 days  DAY 1 Buprenex: 0.015 mg/ kg OR Tramadol: 1mg/lb BID X 3 days PO before melarsomine injection Famotidine 0.5 mg/kg SQ: before melarsomine injection Melarsormine: 0.1 mls/ kg IM  DAY 30 Buprenex: 0.015 mg/ kg OR Tramadol: 1mg/lb BID X 3 days PO before melarsomine injection; DAY 31 Melarsormine: 0.1 mls/ kg IM

Dogs < 22 lb. = 1 inch needle 23G Dogs > 22 lb. = 1.5 inch 22G

Treatment of Heartworm Disease Adulticide therapy LEVAMISOLE Not effective: Kills few adult heartworms and neurological SE May be used as inexpensive treatment for reducing adult burden and clearing mff. from blood Ivermectin and Seleamectin has been shown to reduce adult burden when used over time After adulticide treatment: After 1-2 weeks 0r 4-6 weeks Worm emboli > pulmonary inflammation: coughing, fever, +/- bloody cough (hemoptysis) Cage rest, glucocorticoids, aspirin?? (not if hemoptysis) Adulticide tx. Not recommended in cats

Treatment of Heartworm Disease MICROFILARICIDES Ivermectin (most common): 0.05 mg/kg Given at higher dose as a microfilaricide Monitor for neurologic side effects, anaphylactic shock Should kill microfilaria in ~3 weeks (monitor) 1% ivomec: 0.1 ml/ 20kg or dilute 1:10 and 1ml/ 20kg Milbemycin oxime (interceptor/ sentinel/ trifexis) 0.5mg/kg. Use with caution in HW + dogs: Anaphylactic shock Levamisole (infrequently used) Given for 1 week or longer depending on dosage. MOXIDECTIN IS NOT EFFECTIVE

Treatment of Heartworm Disease PREVENTATIVES: Preventing third-stage larvae from reaching maturity Daily oral preventative Diethylcarbamazine (DEC) Filaribits® Given during mosquito season and two months after Anaphylactic shock and death can occur if given to dog with microfilaria Filaribits Plus® also controls ascarid infections (contains oxibendazole)

Preventatives - Macrolide Ivermectin – Heartgard®, Iverhart PlusTM, Tri-Heart PlusTM 0.006 mg/kg (very low for collies) Macrocyclic lactones “Plus” products also contain pyrantel pamoate (hooks, rounds) Ages 6 months + Side effects include neurologic signs such as salivation, ataxia, and depression Milbemycin oxime - Interceptor® Sentinel® = milbemycin oxime + lufenuron Also effective against hookworms, roundworms, and whipworms and Demodex mites in dogs.

Monthly Topical Preventatives Selamectin - Revolution® Absorbed systemically Dogs: heartworm, adult fleas, ticks, ear mites, sarcoptic mange Cats: heartworm, adult fleas, ear mites, roundworms, hookworms

Monthly Topical Preventatives Moxidectin + imidacloprid = Advantage Multi®, Proheart 6 Heartworm prevention, Flea control, Intestinal parasite prevention Children should not come in contact with application site within 30 minutes of administration Do not use on sick, debilitated, or underweight animals

Parasite Preventatives in Dogs

Parasite Preventatives in Cats

Six-month Injectable Preventative Moxidectin - Proheart® Side effects include neurologic and gastrointestinal signs Withdrawn from the market in September 2004 due to increased reports of adverse side effects including liver and bleeding abnormalities. Reformulated and reintroduced in 2008. Owners must sign a special “Informed Consent” form Age: > 6 months - < 7 years SE: Anaphylaxis, V/D, lethargy, erythma, pruiritis, hyperthermia TX: heartworm, Dilofilaria Dimmitis, Ancylostoma caninum, Uncinara stenocephalia

Ectoparasite Treatment

Ectoparasite Treatment Ectoparasites can be controlled using a variety of different drugs in a variety of different formulations Sprays, Dips, Pour-on, Shampoos, Dusts or powders, Foggers, Oral products, Spot-ons , Injectables Parasites: Flies, grubs, lice: livestock, flies (bots and maggots) – horses, companion animals: fleas, ticks, mange mites Diseases: Zoonotic: Lyme, bubonic plague, RMSF

Lifecycle Flea

Ectoparasite Treatment Organophosphates and Carbamates Pyrethrins and Pyrethroids Amitraz Macrolides Imidacloprid Fipronil Nitenpyram Insect Growth Regulators Insect Repellents

Review - ANS SNS: “Fight/Flight” PNS Epinephrine and norepinephrine Adnergic recoptors: Alpha 1: blood vessels – skin, GI Alpha 2: help regulate release of NE Beta 1: HEART Beta 2: SMOOTH MUSCLE – blood vessels: heart, skeletal muscle; arterioles, terminal bronchioles PNS Acetylcholine Cholinergic receptors Muscarinic: inc. GI stimulation, slow HR, miosis, Nicotinic: found both in PNS and SN

Neurotransmitters and Receptors Smooth/Cardiac muscles may constrict or dilate in response to epi/norepi 1. α1- adrenergic receptors – cause vasoconstriction of skin, GI tract, and kidney [don’t need to digest, make urine, or bleed profusely} 2. β1-adrenergic receptors - increase heart rate and force of contraction 3. β2-adrenergic receptors - cause bronchodilation (relaxation)

Organophosphates & Carbamates MOA: acetylcholinesterase inhibitor Decompose readily in environment: used more in agriculture SLUDDE, bradycardia, and miosis (pinpoint pupils) = classic signs of muscarinic/ nicotinic overstimulation Delayed neurotoxicity syndrome has been reported in people, cats, dogs, and livestock; occurs 1-2 weeks Metabolism OP toxic to myelin sheath > HL ataxia > paralysis Cattle: weakness, depression, droopy ears, bloat TX: Atropine (better for CNS X 10 dose of pre-anesthetic), Pralidoxime reverse OP - human pharmacies Persian cats, sick cats, Whippets, Greyhounds, and certain exotic breeds of cattle are sensitive to Ops. As a general rule, these insecticides should not be used on animals recovering from surgery, sick animals, pregnant animals, or animals considered to be stressed.

Organophosphates & Carbamates Ach – muscarinic receptors Toxicity SLUDDE and miosis Tx: X10 dose of atropine (better for CNS than glycopyrrolate) Pralidoxime: separates OP molecule from Ach-esterase Ach – nicotinic receptors Toxicity Progressive: initially-tremors > progress to shaking > ataxia > paralysis > resp. failure

Glycopyrrolate (Robinul) and Atropine Use Glycopyrrolate in Pregnant animals it does not appreciably cross CNS or placenta Atropine comes in Two concentration: 0.5 mg/mL (injectable-SA) and 2.0 mg/mL (injectable-LA)

Organophosphates & Carbamates Adam’s Flea and Tick Dip®, Spray®, and Tick Dust® Carbaryl (Mycodex shampoo with carbaryl®) Sevin Dust® Cythioate (Proban® tablets and liquid) Diazinon (Escort®) Phosmet (Paramite dip®)

Pyrethrins and Pyrethroids Pyrethrins are natural plant products, derived from chrysanthemum flowers Largest group: OTC, very safe, quick kill Pyrethroids are synthetic pyrethrins: better at killing, -thrin suffix Resmethrin: degraded by UV, leaves odor like stale urine Fenvalerate and permethrin: adhere to nylon/ carpets reduces efficacy Permethrin and deltamethrin: Tick collars: flea and ticks allethrin, tetramethrin, deltamethrin, cyfluthrin,

Pyrethrins and Pyrethroids MOA: Acts on parasite’s nerve cell membrane to disrupt sodium channel, which delays polarization and paralyzes the parasite SE: cats sensitive and can show neurological signs: seizures/paralysis, poison fish Synergists added piperonyl butoxide generally safe, neurotoxicity – cats. Also add insect growth regulators (IGR) Often manufactured with other products such as imidacloprid + pyrethrin(Advantx: not for cats) and as synergist: piperonyl butoxide K9 Advantix, Bio-Spot® for dogs

Formamidines: Amitraz One of the first effective agents available for demodectic mange in dogs. Can repel ticks. MOA: alpha 2 receptor agonist, adnergic (xylazine and detomidine) > decreases norepinephrine > sedation. Inhibits monoamine oxidase hence don’t use with behavior modifying drugs Toxic to cats and rabbits, Use protective clothing and gloves for humans keep it away from children; use in a well-ventilated area SE: Animals may show sedation and incoordination for 24-48 hours after application, pruritus, hypothermia

Amitraz Can be very toxic if ingested by animals or people Reports of toxicity from ingestion of collars Treated with supportive therapy and multiple doses of alpha-2 receptor antagonists: Yohimbine (Yobine) or Atipamezole (Antisedan), Tolazoline (Priscoline, Tolazine)

Amitraz ProMeris® for dogs (synergistic with metaflumizone) Mitaban Dip® PrevenTIC® collar: with IGR for fleas: pyriproxyfen (Nylar) Taktic®EC (cattle) Available in collars, topical treatment, dip, or sponge-on bath.

MACROLIDES Milbemycin oxime Selamectin (Revolution): topical 2002: otic prep. In cats: MilbeMite – Otedectes cynotis Selamectin (Revolution): topical Dogs and cats: fleas, ear mites, hwp Dogs: sarcoptes mange, tick Extra label use: exotics and wildlife

Imidacloprid Advantage® (imidacloprid – fleas) and K9 Advantx (+ permethrin: tick and mosquito, don’t use in cats) Chloronicotinyl nitroguanidine MOA: Insect neurotoxin; blocks receptor site for Ach-nicotinic, thereby blocking transmission of the impulse across the synapse. Marketed for use in both dogs and cats: fleas Poorly absorbed through skin and kills adult fleas on contact Wide margin of safety (toxicity in fish is low) Four week residual activity, topical back of neck

Fipronil Frontline® Fipronil with methoprene (Frontline plus®) MOA: Interferes with GABA receptors - chloride channels of insects (less chloride in neuron), which overstimulates their nervous system causing death Safe for mammals because has low affinity for our GABA receptors Adult fleas, ticks, and chewing lice (on contact); controls sarcoptic mange with repeated treatments. Methoprene is an insect growth regulator, which makes Frontline plus® effective against flea eggs and larvae. Applied topically (absorbed in sebaceous glands); not absorbed systemically Residual activity, even after bathing Not for use in puppies or kittens <8 weeks of age.

Fipronil Also marketed as a measured-dose spray product that is applied at a dose of 3 ml/kg body weight. Container is calibrated to administer precise amount of insecticide to allow accurate dosing. Manufacturer claims that fipronil is unlikely to produce toxicity even if consumed orally. Fipronil binds with the dermis, hair follicles, and sebaceous glands. Has alcohol: salivation if licked and has unpleasant order

Nitenpyram Capstar® MOA: Binds and inhibits Ach-nicotinic receptors Safe for mammals low affinity for receptor (safer than OP) Tablet begins to kill adult fleas within 30 minutes At least 90% fleas killed in 4 hrs. (dogs); 6 hrs. (cats) Can safely give a dose as often as one per day Can use on puppies and kittens older than 4 weeks and weighing more than 2 lb. Only kills adult fleas; should also give insect growth regulator (IGR) to control fleas. SE: intense pruritus for short period: THIS IS OK

Lindane The only chlorinated hydrocarbon currently used in veterinary medicine today. Incorporated in some dog shampoos. Kills insects on contact; directly absorbed into insects and their eggs; also a stomach poison for insects Can produce harmful side effects in people and pets if absorbed in sufficient quantities. Owners should wear gloves, apron, boots Dispose of empty bottles and bath water according to EPA policies Lindane should never be used on cats, puppies <3 weeks, lactating animals, or food animals.

Newer products Spinosad (thanks bacteria): Bad taste Comfortis and Trifexxis MOA: nerve paralysis of fleas at nicotinic Ach receptors and also GABA Kills adult fleas 100% - 4 hrs FAD SE: vomiting To avoid: split dose BID

Insect Growth Regulators Insect growth regulators are compounds that affect immature stages of insects and prevent maturation to adults. Include Insect development inhibitors (IDI) and juvenile hormone mimics (JHM) Insect development inhibitors interfere with development of chitin, which is essential for proper egg formation and development of the larval exoskeleton. The “egg-tooth” used by flea larvae to exit egg is also made of chitin.

Insect Growth Regulators Juvenile hormone mimics prevent fleas from molting to the next stage by interrupting normal molting process. (Fleas need low levels of JH to molt to the next stage; these products mimic the flea’s natural JH) The insect stays in the larval stage and eventually dies. Insect growth regulators do not affect adult fleas. Lufenuron (PROGRAM), methoprene, fenoxycarb, and pyriproxyfen are all IGRs.

Lufenuron Program®: Insect Development Inhibitor The flea component in Sentinel® Interferes with chitin synthesis in flea development Given orally to dogs; orally or SQ to cats: lasts for 6 months Fleas must bite the animal to be exposed to the drug. Effects are noted in 2 weeks hence use with adulticide Also investigated to use for ringworm Lufenuron is distributed to fat and then leaches slowly back into the body fluids, providing a long duration of activity; therefore drug needs to be given only once monthly. SE: vomiting, listlessness

Other IGRs Methoprene (Ovitrol®) is generally regarded as safe. It is found (sometimes as ‘Precor’) in sprays, topical products, and flea collars. Female flea absorbs compounds from skin of animal (deposited by flea collar) and it is incorporated into eggs Flea pupae in carpet are protected from methoprene because it binds to fibers in carpet. FRONTLINE plus with fipronil Pyriproxyfen (Nylar®): JHM - Mostly used in environmental flea control products; may have some activity against adult fleas (but not immediate); more potent than methoprene and fenoxycarb Fenoxycarb was voluntarily withdrawn from the market by the manufacturer in 1996 because of concerns over the results of government testing involving the use of high doses. It breaks down to formaldehyde, a carcinogen.

Insect Repellents Used to repel insects and keep them off of animals Livestock, horses, outdoor dogs: upright ears – German Shepherds and Dobermans May be used in combination with pyrethrins and pyrethroids Include sprays, ear tags, and topicals for ear tips Some products are insecticides as well as repellents Control mosquitoes, flies, and gnats. DEET: Diethyltolamide (Blockade® - Hartz) Combination with fenvalerate; was withdrawn from market for several months because of reports that it caused death in several cats and dogs. Signs of DEET toxicosis include: excitation, tremors, seizures, ataxia, and vomiting.

Insect Repellents Butoxypropylene glycol (Butox PPG ® or VIP® Fly Repellent) Used in equine fly repellents because it provides a shine that is of cosmetic value in show animals Incorporated into flea and tick spray products for use in dogs and cats Can cause dermal irritation if a harness or collar is applied over the area while the haircoat is still wet with spray.

Other External Antiparasitics Rotenone - A.k.a. “Derris Powder” (derived from derris root) Ear Miticide®, Mitaplex-R® Used in dips and pour-on liquids Toxic to fish and swine; consider runoff possibilities when using. D-limonene (VIP Flea Dip and Shampoo®) Derived from citrus peels Has slight insecticidal activity Pleasant smell; provides quick kill; may be used with other products

References Romich, J.A. Pharmacology for Veterinary Technicians, 2nd edition. 2010. Bill, R.L. Clinical Pharmacology and Therapeutics for the Veterinary Technician, 3rd edition. 2006. Beale, Karin. Favorite New Treatment Options in Veterinary Dermatology. Gulf coast veterinary specialists symposium, 2012. http://en.wikipedia.org/wiki/File:Adrenoceptor-Signal_transduktion.PNG