Anthelmintics

Question 1

How does an anthelmintic behave inside the animal?

Answer 1

• Most are absorbed and secreted back into gut
• Many metabolised in liver
• Some enterohepatic recycling may occur
• Urinary and/ or faecal excretion
• Rate of absorption varies from a few minutes to hours
• Small variations is molecular structure can have a big effect on activity

Question 2

What are the three important aspects of metabolism and excretion of anthelmintics?

Answer 2

1. Usually activity increases if metabolism is delayed
2. Some species (goats and deer) metabolise anthelmintics faster than others
3. They affect withholding periods

Question 3

Describe Phenothiazine…

Answer 3

• Released in 1938
• Superceded
• Relatively poor efficacy
• Problems with photosensitisation in cattle and metabolites in urine staining wool

Question 4

Describe Piperazine…

Answer 4

• Originally used for treatment of gout but was ineffective
• In the 1940s, it was used as an anthelmintic for ascaridoids and oxyroids
• GABA agonist
• Many different salts
• Still some used in small animals and horses
• DEC is related and is the original prophylactic against D. immitis

Question 5

What is an action family?

Answer 5

Related chemical that share the same general mode of action

Question 6

What are Benzimidazoles (BZs)?

Answer 6

• All derivatives of thiabendazole
• “azole”
• albendazole, oxfendazole, fenbendazole, oxibendazole, mebendazole
• Insoluble opaque drenches

Question 7

Describe the action/ metabolism of BZs…

Answer 7

• They bind to tubulin and prevent the polymerisation and formation of microtubules in cells
• Later BZs have a longer half-life and have better efficacy
• Some are pro-BZs and rely on being metabolised to their active form
• Broad Spectrum
• Usually need to repeat in monogastrics to maintain levels for long enough
• In ruminants, bind to particulate matter and is slowly released so a single treatment is enough

Question 8

What is the efficacy of BZs in ruminants affected by?

Answer 8

Rumen bypass

Question 9

Describe anthelmintic resistance to BZs…

Answer 9

• In helminths there is loss of tubulin with high affinity sites for BZ means less binding so limited interference with polymerisation
• There are at least 3 helminth genetic loci which all influence the binding of BZs to B-tubulin

Question 10

Describe Levamisole…

Answer 10

• Released in 1960s as a tetramisole
• mixture of d and l enantiomers
• • l- is only one that is active
• Broad spectrum against nematodes
• Soluble
• HCl salt for oral
• Phosphate for injectable
• Cholinergic agonist
• 3-7x [] in sheep
• Too small for horses
• Poorly understood mechanism of anthelmintic resistance
• Sex linked in T. colubriformis
• Autosomal recessive in H. contortus

Question 11

Describe Morantel/ Pyrantel…

Answer 11

• Same mode of action as levamisole
• Broad spectrum especially for nematodes and some against cestodes
• Palmoate salt poorly absorbed
• Higher concentration in caecum and colon
• Tartrate, citrate, embonate all soluble and well absorbed
• Activity against lungworm
• Pyrantel for smallies
• Morantel for ruminants and horses
• Oxantel for dogs against trichuris
• Reasonable safety margin

Question 12

What are the macrocyclic lactones (MLs)?

Answer 12

• Abamectin
• Ivermectin
• Doramectin
• Moxidectin
• Selamectin
• Eprinomectin
• Milbemycin

“ectin”

• Activity against nematodes and arthropods
• No activity against cestodes and trematodes
• Binds to glutamate-gated chloride ion channels
• • Cl- into cells
• • Hyperpolarized
• • Can’t transmit AP
• All lipophilic
• H. contortus & T. circumcincta considered dominant trait for ivermectin
• T. colubriformis considered a semi-dominant trait

Question 13

Describe the anthelmintic resistance to MLs

Answer 13

Anthelmintic Resistance mechanism not yet understood

• Likely to be multigenic
• May involve P-glycoproteins (transmembrane pumps) and move molecules from one compartment to another and change receptors

Question 14

Describe anthelmintic resistance to levamisole…

Answer 14

Poorly understood

• Decreases Ach receptors
• Change from susceptible receptors to others that levamisole doesn’t affect

Question 15

Describe Moxidectin…

Answer 15

• Very lipophilic compared to other MLs
• 2 compartment model - fat depot and circulation
• Get initial + prolonged tail
• H. contortus and Dictyocaulus are easy to kill
• Cooperia and Nematodirus are the dose limiting species
• The prolonged tail means that some worms are exposed to marginally effective levels for prolonged period
• Partly resistant worms survive