Antihelminthics Flashcards
What are antihelminthics?
drugs used for controlling the parasitic worms or helminths that inhabit the organs and tissues of animals:
- GIT (ascarids, tapeworm, flukes)
- respiratory system (Dictyocaulus)
- heart-worm (Dirofilaria)
- muscle (trichinella) and connective tissue
An ideal antihelminthic would have the following 7 properties:
1) A wide therapeutic index (1:6 and more)
2) A broad spectrum of activity against all those classes of parasites that are pathogenic, zoonotic and of an economic importance. Some modern anthelmintics are effective against nematodes, trematodes, cestodes and even against acathocephalic parasites.
3) Efficacy against migrating and hypobiotic (arrested) larvae of nematodes, immature flukes and scolexes of cestodes as well against adult worms.
4) A short residence time in the milk or tissue in case of treating of food animals, i. e. a short withdrawal period. In non-foodstuffs animals, prolonged presence of drug can be advantageous by providing an extended protection against the reinfection.
5) No unpleasant side-effects or hazards to the animal.
6) It should be compatible with other therapeutic agents (interactions), easy to be administered and stable (i. e. not decomposed by light, temperature, moisture etc.) and does not require repeated administrations.
7) Economic aspects. Low price of drug (treatment should be significantly cheaper than price of animal esp. in decorative pets).
Describe wide therapeutic index in terms of antihelminthics
A wide therapeutic index (1:6 and more). It is a ratio of therapeutic dose to the maximum tolerated dose. A therapeutic index of 1:2 is very narrow, indicating that twice the dose required to destroy the parasite will be toxic to the host. A safety
margin of at least six-fold is expected of modern anthelmintics.
Describe the basic principles of antihelminthic treatment
1) First to identify the parasitic infection (nematode, cestode etc.)
2) To select an appropriate drug to treat this condition in regard to species of parasite, but also to animal, for example, food animal, animals in lactation, pregnancy (teratogenicity), exhausted animals, high body temperature, extent of infestation by helminths.
3) To determinate the dose of drugs (higher dosage against immature forms)
4) The choice of the best way of administration
5) The time of treatment, for example in calves antinematodal drugs are recommended in midsummer, when pastural larval infestations reach their peak.
6) Repeated administrations should be done according to the protection properties of used anthelmintics or according to the possibility of reinfection in grazing animals (for example ivermectin activity persists for several weeks after dosing). Modern technology has produced single-dose boluses which reside in the rumen after dosing and offer protection of animals over the entire grazing period.
When is repeated administration absolutely necessary?
in the case of drugs without activity against immature forms of parasites (piperazine).
How can antihelminthics be administered?
- Anthelmintics of very low toxicity are administered in diet (benzimidazoles) or in drinking water. They must be stable in water.
- Orally as a drench (sheep), tablets, boluses, pills, granules by esophageal tube in individual animals, what provides an exact dosage of the drug.
- Parenterally ex. levamisole and ivermectin.
Describe the 4 mechanisms of action of antihelminthics
- inhibitors of tubulin polymerization - benzimidazoles and probenzimidazoles (which are metabolized in vivo to active benzimidazoles and thus act in the same manner)
- uncouplers of oxidative phosphorylation - salicylanilides and substituted phenols
- inhibitors of enzymes in the glycolytic pathway – clorsulon
- interfere with neuromuscular apparatus (cholinomimetic effect, increasing of GABA release,..) – organophosphates, macrocyclic lactones
Resistance of Haemonchus contortus and Nematodirus spp.
The frequency of anthelmintic treatment in sheep, as for example in Australia against Haemonchus contortus (monthly) is ideally suited to the development of resistance. Benzimidazole resistance is in direct relationship to the frequency of dosing.
Resistance of H. contortus and Nematodirus spp. against thiabendazole was detected already only 3 years after this product was introduced to the therapy. Later it was found that cross-resistance was developed between thiabendazole and its newer derivatives.
How to prevent resistance?
Sensible application of modern anthelmintics (ivermectin, albendazole etc.) provides an opportunity to control the resistance problem.
Therefore, the best way to prevent the development of worm resistance is to minimize the frequency of dosing, to alternate the treatment between different classes of anthelmintics or take advantage of the prophylaxis offered by slow-release rumen boluses and especially to make full use of clean pasture.
Which factors predispose the development of drug resistance?
- using anthelmintics below their recommended dose,
- continued use of a single type of anthelmintic, or
- excessive treatment of animals.
Briefly describe the pharmacokinetics of antihelminthics
Although many helminth parasites reside in the lumen or close to the mucosa, others live at sites such as the liver and lungs; for action against these, absorption of drug from the GI tract, injection site, or skin is essential.
After administration, anthelmintics are usually absorbed into the bloodstream and transported to different parts of the body, including the liver which is the usual site of metabolism of anthelmintics - oxidation and cleavage reactions commonly occur. They are then eventually excreted in the faeces and urine.
Describe the division of antihelminthics
- / Antinematodics - antiparasitics against roundworms: Trichostrongylus, Haemonchus, Ascaris, Nematodirus, Strongylus, etc.
- / Antitrematodics - antiparasitics effective against flukes from genera: Fasciola, Paramphistomum, Paragonimus, Dicrocoelium, Opisthorchis
- / Anticestodics - antiparasitics against tapeworms: Taenia, Echinococcus, Dipilidium, Moniezia, etc.
- / Antiacanthocephalics
Describe the division of antinematodal drugs according to their chemical structure and list the active substances
1) Imidazoles
a) benzimidazoles (thiabendazole and its derivatives, albendazole, fenbendazole, flubendazole mebendazole, oxfendazole, oxibendazole, parbendazole),
b) probenzimidazoles (febantel, netobimin),
c) imidazothiazoles (levamisole, tetramisole)
2) Macrocyclic lactones (avermectins, milbemycins),
3) Tetrahydropyrimidines (pyrantel, morantel, oxantel and others),
4) Organophosphorous compounds (dichlorvos, haloxon, trichlorfon, coumaphos, etc.),
5) Heterocyclic compounds (piperazine, diethylcarbamazine, phenothiazine),
6) Miscellaneous nematocidal compounds (emodepsid, nitroscanate)
Name the 3 subgroups of imidazoles
Benzimidazoles, probenzimidazoles, imidazothiazoles
Name the active substances of benzimidazoles
thiabendazole and its derivatives, albendazole, fenbendazole, flubendazole mebendazole, oxfendazole, oxibendazole, parbendazole
What was the first benzimidazole introduced to therapy?
Thiabendazole
Use of benzimidazoles and their safety
The benzimidazoles are a large chemical family used to treat nematode and trematode infections in domestic animals. They also have limited activity against cestodes.
With few exception benzimidazoles are very safe anthelmintics having a high therapeutic index, but care needs when administered in pregnant animals (embryotoxicity and teratogenicity).
Disadvantage of benzimidazoles
development of resistance (thiabendazole within 3 years) and also cros-sresistance to other benzimidazoles, when used in frequent intervals throughout the year.
Absorption of benzimidazoles
With a few exceptions, eg, albendazole, oxfendazole, only limited amounts of any of the benzimidazoles are absorbed from the GI tract of the host. The limited absorption is probably related to the poor water solubility of these drugs.
The little absorption that occurs is generally rapid.
How do benzimidazoles reenetr the GIT after being absorbed?
Many of the benzimidazoles and their metabolites re-enter the GI tract by passive diffusion, but the biliary route is the most important pathway for secretion and recycling of benzimidazoles to the GI tract.
Which spp. are benzimidazoles most effective in?
Benzimidazoles are more effective in ruminants and horses, in which their rate of passage is slowed by the rumen or cecum. The rumen acts as a drug reservoir from which plasma concentrations can be sustained, slowing the passage of unabsorbed drug through the GI tract.
Benzimidazole mechanism of action
act primarily by binding to nematode β- tubulin. It prevents its dimerization with α-tubulin and polymerization of tubulin oligomers into microtubules.
Microtubules are essential structural units of many organelles and are necessary for numerous cellular processes, including mitosis, protein assembly, and energy metabolism.
Describe thiabendazole
Thiabendazole is the first of this generation still used against adult and larval nematodes.
Describe albendazole
Activity: It is effective against important nematodes and their larvae including hypobiotic or inhibited forms and also against cestodes, and some flukes.
Use: Widely for treating ruminant roundworms and flukes in the form of intraruminal bolus.
Albendazole dose
5-7.5 mg/kg
Describe fenbendazole
It is active against all important nematodes including the inhibited larvae and also against some tapeworms.
Describe flubendazole
Flubendazol is used for treating round worms only in pigs
Describe mebendazole
Mebendazole is effective against roundworms, tapeworms and also cestode’s larvae, it is not generally used in cattle.
Describe oxfendazole
It is effective against nematodes and their inhibited larvae and cestodes.
Oxfendazole is a sulphoxide metabolite of fenbendazole & is probably responsible for the activity of both these anthelmintics.
This means that fenbendazole is metabolized to oxfendazole.
Describe oxibendazole
Against GI and lung worms (nematodes) it is usually employed in horses
Describe parbendazole
It was a first derivate of thiabendazole, but is less widely used today.
It is effective against most GI nematodes and lungworms.
Name the active substances of imidazothiazoles
Levamisole, tetramisole
What is levamisole?
Levamisole is the l-isomer of tetramisole. It is a water soluble substance, which may be administered orally and parenterally
Levamisole mechanism of action.
Levamizole as a cholinergic agent causes paralysis of worms but also inhibits the enzyme fumarate reductase.
Levamisole use
is effective against adult and larval GI roundworms and lungworms. It has a rapid effect on parasites, expelling most worms within 24 h. It is important for treatment the benzimidazole-resistant worms.
It has also garnered much interest as an immunostimulant in the adjunctive therapy of various neoplasms.
Name the active substances of probenzimidazoles
Febantel and Netobimin
What are probenzimidazoles?
Two probenzimidazole compounds, febantel and netobimin, exist in the form of pro-drugs and must be metabolized in the GI tract to the biologically active benzimidazole carbamate nucleus.
Describe febantel
It is a precursor of fenbendazol so its activity is the same of that of fenbendazol
Describe netobimin
It is a precursor of albendazol.
Define and describe macrocyclic lactones
macrocyclic lactones (avermectins and milbemycins) are products or chemical derivatives of soil microorganisms belonging to the genus Streptomyces.
They have a potent, broad antiparasitic spectrum at low dose levels.
Use of macrocyclic lactones
They are active against many immature nematodes (including hypobiotic larvae) and arthropods (ectoparasites).
Are NOT effective against cestodes and trematodes.
Describe absorption and distribution of macrocyclic lactones
Are well absorbed when administered PO or parenterally. Regardless of the route of administration, macrocyclic lactones are extensively distributed throughout the body and concentrate particularly in adipose tissue. Effective levels are reached in the GI system, lungs, and skin.
The association of macrocyclic lactones with digesta affects absorption.
Liver tissue contains the highest residue for the longest time, reflecting the route of elimination. Although the magnitude of lipophilicity differs among chemical types, the limited vascularization and slow turnover rate of body fat and the slow rate of release or exchange of drug from these lipid reserves can prolong the residence of drug in the peripheral plasma.
Describe avermectins
Since the discovery of benzimidazoles, avermectins represent the biggest breakthrough in parasite control.
Macrolide endectocides avermectins and closely related milbemycins are produced by actinomycete micro-organisms Streptomyces avermitilis.
They are highly potent with wide spectrum activity against nematodes and ectoparasitic arthropods, require very small doses, with long persisting activity and may be administered orally or parenterally with acceptable safety margin, without embryotoxicity and teratogenicity.
Name the avermectins
Ivermectin, Doramectin, Selamectin, Eprinomectin
Use of ivermectin
Ivermectin is approved in horses for the control of large strongyles (adult), small strongyles, pinworms, ascarids, hairworms, large-mouth stomach worms, neck threadworms (microfilaria), bots, lungworms, intestinal threadworms, and summer sores secondary to Hebronema or Draschia spp.
In cattle, ivermectin is approved for use in the control of gastrointestinal roundworms, lungworms, cattle grubs, sucking lice, and mites (scabies).
In swine, ivermectin is approved for use to treat GI roundworms, lungworms, lice, and mange mites.
In reindeer, ivermectin is approved for use in the control of warbles.
In dogs and cats, ivermectin is approved for use as a preventative for heartworm. It has also been used as a microfilaricide, slow-kill adulticide, ectoparasiticide, and endoparasiticide.
Ivermectin mechanism of action
Ivermectin enhances the release of gamma amino butyric acid (GABA) at presynaptic neurons.
GABA acts as an inhibitory neurotransmitter and blocks the post- synaptic stimulation of the adjacent neuron in nematodes, or the muscle fiber in arthropods. By stimulating the release of GABA, ivermectin causes paralysis of the parasite and eventual death.
As liver flukes and tapeworms do not use GABA as a peripheral nerve transmitter, ivermectin is ineffective against these parasites.
When NOT to use ivermectin
ivermectin should not be used in breeds susceptible (Collies, Shelties, Australian shepherds, Long-haired Whippet etc.) to the MDR1 gene mutation (reduced production of p-glycoprotein) unless the patient has been tested and found not to have the gene defect. A specific test for identifying dogs that have this gene defect is now available.
What dosage form is commonly used to give ivermectin to horses?
Usually pastes that are administered p.o.
Doramectin use
potentially used for generalized demodicosis in small animals
What are selamectin and eprinomectin?
They are topical avermectin antiparasiticides for cattle, dogs and cats. The topical administration is along backline in a narrow strip from the withers to the tailhead.
Name the active substances of milbemycins
Moxidectin and milbemycin oxime
Moxidectin use
It is a chemically modified derivative of nemadectin (a fermentation product).It has a broad range of activity against nematode and arthropode parasites
Use of milbemycin oxime
It is a fermentation product and has activity against certain arthropods and nematodes.
Is used to prevent heartworm disease and Ancylostoma spp. of dogs.
Name the active substances of tetrahydropyrimidines
Morantel, Oxantel, Pyrantel
Tetrahydropyrimidines mechanism of action
Their primary mode of action is to affect the worm neuromuscular system leading to paralysis and death. Tetrahydropyrimidines have been used to control of benzimidazole resistant worms, but like levamisole, resistance has been demonstrated also against these drugs.
Morantel use
The tartrate of morantel is used in form of bolus (so called “paratect” slow release bolus) placed in rumen. The active substance is slowly released from bolus protecting the animal for 90 days against adult and larval nematodes, but not lungworms in cattle.
Oxantel use
It is effective only against Trichuris vulpis usually used in combination with pyrantel.
Pyrantel use
It is usually used as the pamoate salt for treating nematodes in dogs.
At double dose it is effective against horse tapeworms.
Active substances of organophosphorus compounds
Dichlorvos, Haloxon, Trichlorphon
Organophosphorus compound mechanism of action
Their mode of action is to inhibit the enzyme acetylcholinesterase of worms leading to paralysis and death. But also deplete the ACHE of the host, and so are not always well tolerated by mammaIs.
Why are organophosphorus compounds not used as much anymore?
However, because of their relative toxicity, limited efficacy against immature stages, narrow margin of safety, and contamination of the environment through fecal excretion, their use has declined.
Dichlorvos use
Dichlorvos is particularly useful in pigs against all major adult nematodes and was one of the first broad-spectrum anthelmintics to be used in this species.
Haloxon use
It is used against GI nematodes in pigs and horses
Trichlorphon use
It is a pro-drug of dichlorvos used mainly in horses against certain GI nematodes and bots
Heterocyclic compound active substances
piperazine, diethylcarbamazine, phenothiazine
Heterocyclic compound mechanism of action
Worms suffer from hyperpolarization of their muscles what produces paralysis and the worms are eliminated with faeces.
The compouds exert „curare-like“ effects on susceptible nematodes, thereby paralyzing or narcotizing the worm and allowing it to be passed out with the faeces.
The neuromuscular blocking effect is believed to be caused by blocking acetylcholine at the myoneural junction. In ascarids, succinic acid production is also inhibited.
Piperazine use
Piperazine is still used against ascarid and oxyurid worms with 95 - 100% of effectivity upon adult forms.
Diethylcarbamazine use
It is a derivative of piperazine with activity against lung- worms but it is more important in the control of canine heartworm disease
In areas, where heartworm is endemic dietylcarbamazine is used for prophylaxis by daily treatment
Phenothiazine use
Not used often
Miscellaneous nematocidal compounds
Emodepside, Nitroscanate
Emodepside use
It is currently available in some countries in combination with praziquantel (for treatment of cestode infections) as a topical formulation
for the treatment of ascarids and hookworms in cats
and as an oral formulation for the treatment of ascarids, hookworms, and Trichuris in dogs
For dogs, emodepside is also available in combination with toltrazuril as an oral suspension for coccidia and GI nematode control.
Nitroscanate use and mechanism of action
Nitroscanate, like the substituted phenols, probably acts by uncoupling oxidative phosphorylation.
It is used in small animals (dogs) against Toxocara, Toxascaris, Taenia, Dipylidium, Ancylostoma, Uncinaria, and Echinococcus spp.
What are antiparasitics effective against flukes called?
Antitrematodal dugs or flukicides
What are flukes and which animals are they commonly a problem in?
Flukes can be seriously harmful to grazing livestock, especially sheep, but also cattle, particularly in humid regions that offer an adequate environment for the intermediate hosts (typically snails and other mollusks).
Flukes can occur in traditional pig and poultry production, but are usually not an issue in industrial operations.
Flukes are seldom a problem for pets, especially in urban environments nor for horses.
In fact, there are almost no veterinary medicines for controlling flukes on dogs, cats or horses, very few for pig and poultry, but numerous brands for sheep and cattle.
Classification of antitrematodal drugs and their active substances
- Halogenated salicylanilides: oxyclozanide, closantel, rafoxanide
- Halogenated phenols: nitroxynil, niclofolan
- Phenoxyalcans: diamphenethide
- Benzimidazoles: albendazole, luxabendazole, triclabendazole
- Organophosphates: trichlorphon, bromphenophos
Halogenated salicylanilide mechanism of action
Salicylanilides are uncouplers of the oxidativephosphorylation in the cell mitochondria, which disturbs the production of ATP. This seems to occur through suppression of the activity of succinate dehydrogenase and fumarate reductase, two enzymes involved in this process. This impairs the parasites motility and
probably other processes as well
Oxyclozanide use
It is active against adult liver flukes and 6 weeks old larvae
Often mixed with broad-spectrum nematocides.
Closantel use
It is an oral and parenteral fasciolicide of ruminants. It is active against adult and juvenile flukes, dirofillaria, fly larvae, mites, ticks and some cestodes.
Rafoxanide use
It is efficient against both adults and larval stages.
It can be use also in another parasitosis (Gastrophillus spp., Haemonchus spp., etc.).
Halogenated salicylanilides active substances
oxyclozanide, closantel, rafoxanide
Halogenated phenols active substances
nitroxynil, niclofolan
Halogenated phenols compared to halogenated salicylanides
They are tolerated worse than halogenated salicylanilides.
Niclofolan use
It is active against adult and juvenile flukes, Paraphystomum cervi and larvae Hypoderma bovis in ruminants, pigs and horses.
Nitroxinyl use
It is a low spectrum flukicide not very much used on cattle, sheep and
goats because is destroyed by ruminal microorganisms so can only be used as an injection.
Active substance of phenoxyalcans
diamphenethide
Diamphenethide use
It is effective especially against very young flukes (from 1st day) in sheep, but it is inactive or less active in cattle.
Benzimidazole active substances
albendazole, triclabendazole
Triclabendazole use
It differs from other benzimidazoles in spectrum of activity, i. e. very active against liver fluke from 1 st day old to adult forms and has no antinemathodal activity.
Why are organophosphates not used often anymore as antitrematodal drugs?
Trichlorphon and bromphenophos today are used only very occasionally because of their low activity (resistancy) & high toxicity.
Which antitrematodal drug is effective against early immature, immature and mature liver flukes?
Check iPad pic (triclabendazole)
Name some miscellaneous trematocidal compounds
Benzenesulfonamides, Clorsulon
Clorsulon use
is a sulfonamide used against adult liver flukes in combination with ivermectin.
Antiparamphistomosis drugs use and active substances
Rumen fluke (Paraphistomum spp.) infections are common in cattle and sheep. Adult flukes attach to the rumen wall. Intestinal paramphistomosis respond well to treatment with drugs effectives against liver fluke and/or cestode infection in ruminants: niclosamide, niclofolan, resorantel and bithionol.
Antiparagonimosis drugs use and active substances
Lung fluke (Paragonimus spp.) infections occur in dogs and cats in the Americas and in the Far East. Apparently efficacious are bithionol, praziquantel, albendazole and fenbendazole,
What are the 2 types of anticestodal drugs called?
Anticestodal drugs are referred to as taeniacides (cause death) or as taeniafuges (facilitate tapeworm expulsion).
What is the aim of anticestodal treatment?
The aim of satisfactory treatment of tapeworm infection is the complete removal of the parasites, including the scolexes, by which the parasite is attached to the mucosa. Today a taeniacidal action is required.
Characterize the newer anticestodal drugs
The newer modern anticestodal drugs remove also scolexes, have activity in various animal species and are tolerated well.
What are the most important anticestodal drugs?
synthetic compounds: niclosamide, praziquantel, epsiprantel, bunamidine, resorantel, dichlorphen, nitroscanate
Describe niclosamide and it’s use
It is a salicylanilide derivative used as an oral tapeworm remedy.
Activity: It is effective against cestodes Echinococcus, Taenia spp., Dipylidium caninum in dogs and cats and in ruminants against intestinal flukes such as Paramphistomum spp. In some countries it is also used in cattle and sheep against Moniezia benedeni infections and in horses against species of Anoplocephala magna.
Niclosamide mechanism of action
Mode of action is based on an attacking the proteosynthesis of worms and inhibition of
oxidative phosphorylation.
What is praziquantel and what is it’s use?
It is an excellent taenicide belonging to the chemical class of the isoquinolines. It is very much used in dogs and cats but it is less used in livestock or birds.
Already in very low doses it is effective against larvae from 4 days old. It is active against scolexes, which are expulsed from GIT. In higher doses eliminates 90% of Dicrocoelium dendriticum (small hepatal fluke).
Praziquantel mechanism of action
It affects the permeability, facilitates Na a Ca ions to penetrate through the membrane in muscles. As consequence the worms are paralysed and die. It also affects carbohydrate metabolism and causes a vacuolization of the tegument.
How often must Niclosamide and Praziquantel need to be administered for prophylaxis.
Praziquantel and niclosamide are administered in dogs 2-4 times a year for prophylaxis to avoid the infection by cestodes.
Praziquantel toxicosis and when not to use
Toxicity occurs at 40 times the therapeutic dose in dogs, the only toxic symptoms seen is occasional vomiting. The injection is painfull. It is not recommended to be given to puppies under 4 weeks of age and kittens under 6 weeks.
Name the combinations of Praziquantel with other active substances
praziquantel + pyrantel
praziquantel + pyrantel + febantel
Praziquantel + emodepside
Describe epsiprantel and its use
It is a isoquinoline derivative very potent and safe novel tapeworm remedy with excellent oral activity against tapeworms in dogs, cats, sheep and horses.
Describe dichlorphen and its use
It is a phenol derivative, extremely well tolerated in dogs and cats, but only of narrow spectrum activity. It has moderate activity against Taenia spp. and Dipylidium spp. in dogs, but is ineffective against Echinococcus spp.
Worms are killed in the gut, disintegrated prior to expulsion.
Describe nitroscanate and what animals is it used in?
It is a phenylthiocyanate derivative active against tapeworms in dogs. It may be used in young puppies, pregnant and lacting bitches.
Bithionol use
It is a phenolic compound used for treatment of tapeworm infection in dogs, cats, poultry and ruminants.
It is highly effective in dogs against Taenia spp., but less against Dipylidium spp. In poultry against Raillietina spp., in ruminants against Moniezia spp. and Paramphistomum spp.
Describe resorantel and its use
It is a resorcylanilide derivative with highly activity against Moniezia spp. in ruminants and also against Paramphistomum spp.
Name some acanthocephalic drugs
dichlorophen, bithionol, thiabendazole, albendazole, niclosamide.
However in last years there are in verification also newer generations of agents tested for the effectivenes against acanthocephala (loperamid).
