1. Anthelmintics Or ‘Why I like drugs” Nick Sangster Faculty of Veterinary Science University of Sydney

2. Worms

3. Objectives Understand the need and market for anthelmintic drugs Describe the features of the major anthelmintic groups Explain spectrum of activity

4. Antiparasitic drugs Anthelmintics – helminths, worms Antiprotozoals – Protozoa Ectoparasiticides – insects and acarines Actions and use differ, but the same principles apply to control and registration

5. Internet Resources www.sheepwormcontrol.com Vich.eudra.org www.apvma.gov.au http://www.worminfo.org/decision_analysis /tropical_worm_world/

6. 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.

7. 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

8. The world animal product market 1996 $M USDLivestockCompanion Parasiticides14031295 Performance 310 - Antimicrobial1705 355 Other pharms 795 585 Biologicals1585 610

9. % Australian market

10. 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

11. Discovery and dose rates

12. 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

13. Aspects of commercial anthelmintics Establishing a need/market Research Screening Refinement Development Marketing Technical support

14. Anthelmintic modes of action ClassexampleMOA BenzimidazolesAlbendazoleTubulin binding and cellular disruption TetrahydropyrimidineLevamisoleNicotinic-like agonists OrganophosphatesDichorvosAcetylcholine esterase inhibitors PiperazinesPiperazineGABA agonists Macrocyclic lactonesIvermectinGluCl - potentiators PraziquantelEnhance Ca ++ permeability SalicylanilidesClosantelProton ionophores

15. 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)

16. 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

17. Piperazine Tablet of liquid for dogs Used for roundworm control Acts like GABA to relax body muscle and paralyse worms

18. Macrocyclic lactones Ivermectin, moxidectin etc. Broadspectrum including ectoparasites Oral, injection or backline Act on GluCl - channels to cause paralysis of pharynx and body muscle

19. Salicylanilides Closantel Blood sucking parasites (Haemonchus and Fasciola) Oral for sheep Uncouples energy generation in worm mitochondria

20. Spectrum of activity

21. 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?