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
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?
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.
Thiabendazole is the first of this generation still used against adult and larval nematodes.
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.
It is active against all important nematodes including the inhibited larvae and also against some tapeworms.
Flubendazol is used for treating round worms only in pigs
Mebendazole is effective against roundworms, tapeworms and also cestode’s larvae, it is not generally used in cattle.
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.
Against GI and lung worms (nematodes) it is usually employed in horses
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
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.
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.
It is a precursor of fenbendazol so its activity is the same of that of fenbendazol
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.
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