Anthelmintics

Or ‘Why I like drugs”

Nick Sangster

Faculty of Veterinary Science

University of Sydney

Worms

Objectives

• Understand the need and market for anthelmintic drugs

• Describe the features of the major anthelmintic groups

• Explain spectrum of activity

Antiparasitic drugs

• Anthelmintics – helminths, worms

• Antiprotozoals – Protozoa

• Ectoparasiticides – insects and acarines

Actions and use differ, but the same principles apply to control and registration

Internet Resources

• www.sheepwormcontrol.com

• Vich.eudra.org

• www.apvma.gov.au

• http://www.worminfo.org/decision_analysis/tropical_worm_world/

What are anthelmintics?

• Anti helminth drugs

• Act to kill/remove/control– Nemathelminthes (roundworms)– Platyhelminthes (flatworms)

• Used widely in animal and human health

• A range of chemical types with different actions and efficacy.

Why know about anthelmintics?

• Dispel the myth ‘but they have a drug for that’• Know how to read and understand the label• Know enough to make usage decisions in the face

of:– Drug resistance (when drugs stop working)

– Off label use (to use in an animal outside registration)

• Antiparasitics major part of market • This sector employs a lot of vets

The world animal product market 1996

$M USD Livestock Companion

Parasiticides 1403 1295

Performance 310 -

Antimicrobial 1705 355

Other pharms 795 585

Biologicals 1585 610

% Australian market

Ectoparasiticides

Anthelmintics

Vaccines

Vitamins

Antibacterials

Coccidiostats

Others

Challenges in anthelmintic discovery

• Kill (or remove) worms in a single dose• Cannot target cell division• Parasite phylogenetically close to the host

e.g.– some of the same neurotransmitters, – same ribosomal machinery

• There are some very good drugs on the market

Discovery and dose rates

0.1

1

10

100

1000

1920 1940 1960 1980 2000 2020

Year

do

se r

ate

mg

/kg

Thiabendazole Levamisole

Ivermectin

Phenothiazine

Requirements of anthelmintics

• Effective, safe, non toxic to consumer.• Narrow spectrum, broad spectrum• Stock Medicines Act 1989 and vets

– Anyone can give stock medicines to non-food producing animals (we eat horses!)

– Only vets can vary label directions in food producers but MUST supply (in writing) species, withholding, dose rate, frequency of treatment, manner of administration.

– No one can use an unregistered stock medicine except under permit or order

Aspects of commercial anthelmintics

• Establishing a need/market

• Research

• Screening

• Refinement

• Development

• Marketing

• Technical support

Anthelmintic modes of action

Class example MOA

Benzimidazoles Albendazole Tubulin binding and cellular disruption

Tetrahydropyrimidine Levamisole Nicotinic-like agonists

Organophosphates Dichorvos Acetylcholine esterase inhibitors

Piperazines Piperazine GABA agonists

Macrocyclic lactones Ivermectin GluCl- potentiators

Praziquantel Enhance Ca++ permeability

Salicylanilides Closantel Proton ionophores

Benzimidazoles

• Many members such as fenbendazole and albendazole

• Effective against nematodes (adults and larvae) and some flukes

• Given as oral liquids to all hosts• Act by binding to tubulin leading to loss of

cell transport and shape• (Triclabendazole- flukicide)

Levamisole

• Levamisole and pyrantel• Effective against nematodes• Given as an oral liquid

(levamisole-sheep; pyrantel-dogs)

• Act on Acetylcholine receptors of worms to cause paralysis

Piperazine

• Tablet of liquid for dogs

• Used for roundworm control

• Acts like GABA to relax body muscle and paralyse worms

Macrocyclic lactones

• Ivermectin, moxidectin etc.

• Broadspectrum including ectoparasites

• Oral, injection or backline

• Act on GluCl- channels to cause paralysis of pharynx and body muscle

Salicylanilides

• Closantel

• Blood sucking parasites (Haemonchus and Fasciola)

• Oral for sheep

• Uncouples energy generation in worm mitochondria

Spectrum of activityAnthelmintics for dogs and cats

COMPOUND chemical class DOSE (mg/kg)

Piperazine piperazine 80-100 + +/-Pyrantel tetrahydropyrimidine 14 (56 in cats) + +Oxantel tetrahydropyrimidine 15 +Febantel pro-benzimidazole 25 + + +Mebendazole benzimidazole 20 (3-5 days) + + + +Flubendazole benzimidazole 22 + + + +*Fenbendazole benzimidazole 50 (3d) + + + + +aLevamisole Imidothiazole 5 or 10 + + + +/- +Nitroscanate Isothiocyanate 50 + + + +Arsenamide Arsenical 2 bid, 2d. IV +Melarsomine Arsenical IM +Thiacetarsamide Arsenical 2.2 bid, 2d. IV +Diethylcarbamazine piperazine 10 +Milbemycin oxime macrocyclic lactone 0.5 + + + +Ivermectin macrocyclic lactone 0.006 +*Ivermectin macrocyclic lactone 0.05 + +Moxidectin macrocyclic lactone 0.003 +Selamectin (dogs) macrocyclic lactone 6 +Selamectin (cats) macrocyclic lactone 6 + + +Praziquantel 5 or b + + +Niclosamide 100 + +

a, for Aelurostrongylus in cats; b, 20 mg/kg for Spirometra; * off label use; check all labels and dose rates before use.

Dipylidium

Taenia

Echinococcus

Asc

arid

oids

Ancylostoma

Trichuris

Lung

wor

ms

Dirofilaria

adu

lts

Dirofilaria

larv

ae

Dirofilaria

mic

rofil

aria

e

New chemicals on the horizon

• Bay 44-4400– Novel mode of action– GI nematodes at 1 mg/kg

• 2-deoxyParaherquamide– Cholinergic antagonist (novel action)– GI nematodes– Sheep industry product?