ANTHELMINTICS FOR ANIMAL USEAnthelmintics/ Antihelminthics are drugs that expel parasitic worms (helminths) from the body, by either stunning or killing them. - They may also be called vermifuges (stunning/expelling) or vermicides (killing). Ideal anthelmintic characteristics: • wide margin of safety • broad spectrum of activity • selectively toxic to the parasite • Good efficacy • Easy to administer without complex dosing schedules • Short residual effects in edible products • Stable to chemical and environmental variables • Economical • considerable activity against immature (larval, ovoid) and mature stages of helminthes The selective toxicity to the parasite,is achieved either by inhibiting special metabolic processes of worms, or by inherent pharmacokinetic properties of the compound that cause the parasite to be exposed to higher concentrations of the anthelmintic than the host cells. Helminths are divided into two major groups:Nematodes: cylindrical, nonsegmented worms commonly called roundworms; Platyhelminths: flattened worms that are subdivided into two groups: Cestodes (tapeworms) and Trematodes (flukes) CLASSIFICATION OF ANTHELMINTICS I. BASED ON ANTHELMINTIC SPECTRUM • Drugs acting against roundworms (nematodes)- Antinematodals • Drugs acting against apeworms (cestodes)- Anticestodals • Drugs acting against flukes (trematodes)- Antitrematodals II. BASED ON STRUCTURE Benzimidazoles 11. Bisphenolic compounds Probenzimidazoles 12. Sulphonamides Imidazothiazoles 13.Natural organic compounds Isoquinoline and benzazepin derivatives 14. Inorganic compounds Organophosphates 15. Hexyloixynaphthamidines Piperazines 16. Miscellaneous Tetrahydropyrimidines Salicylanilides and substituted phenols Macrocyclic lactones (Avermectins and milbemycins) 10. Halogenated hydrocarbons 1. 2. 3. 4. 5. 6. 7. 8. 9. ANTI NEMATODALS Group Benzimida zoles Example Albendazole ANTI TREMATODALS Group Halogenated hydrocarbon s ANTICESTODALS Example Praziquantel Epsiprantel Probenzi midazoles Febantel Imidazothi azoles _ Tetrahydr opyrimidi nes Levamisole Pyrantel pamoate Example Group Carbontetrachlori Prazinoisoqu de inolones Hexachloroethane Hexachloroparax ylene Salicylanilide Closantel, Salicylanilid s Resorantel es Rafoxanide Ciloxanide Oxyclozanide Brotianide Diamphenethide Nitrophenols Niclofolan Substituted Disophenol phenols Nitroxynil Bisphenolic Hexachlorophene Natural compounds Bithional organic sulfoxide compounds Bromsalans Niclosamide Resorantel Dichlorophen Nitroscanate AlkaloidsArecholine Nicotine Cucurbitine; Kamala, Filicic acid(Dryopte res filiximas) Tin oxide Lead arsenate Scolaban Bunamidine Fenbendazol e Albendazole Mebendazole Oxfendazole Febantel Piperazine s Salicyla nilides Substitute d phenols Piperazine DEC Closantel, Benzimidazol es Probenzimid azoles Sulphonamid es Albendazole Triclabendazole Luxabendazole Netobimin Inorganic compounds Hexyloixyna phthamidine s Benzimidazo les Nitroxynil Clorsulon Macro Ivermectin, milbemycine cyclic lactones Organoph Haloxon, Dichlorovos osphates Miscellane Phenothiazine,Disophenol ous Thiacetarsamide, Dithiazine Probenzimid azoles 1. BENZIMIDAZOLES (BZ) AND PROBENZIMIDAZOLES (PBZ) a. Thiazolil-benzimidazoles- Thiabendazole , Cambendazole b. Benzimidazol-carbamates-(5-keto BZs, Sulphid-BZs)Flubendazole, Fenbendazole, Mebendazole, Oxfendazole sulphoxide),Parbendazole, Oxibendazole, Ricobendazole sulphoxide) , Thiophanate and Triclabendazole c. Probenzimidazoles (pro-drugs) Febantel→Fenbendazole→Oxfendazole (Oxfenbendazole) Netobimin→Albendazole→Ricobendazole Thiophanate→Lobendazole Albendazole, (Oxfendazole (Albendazole Mechanism of actionPrimary effect: • Inhibition of tubulin polymerization; by binding to the nematode tubulin, thus inhibiting its polymerization or assembly into microtubules, leading to degenerative alterations in the tegument and intestinal cells of the worm Secondary effect: • Inhibition of cellular transport and energy metabolism, are consequences of the depolymerization of microtubules. • The loss of the cytoplasmic microtubules leads to impaired uptake of glucose by the larval and adult stages of the susceptible parasites, and depletes their glycogen stores. • Degenerative changes in the endoplasmic reticulum, the mitochondria of the germinal layer, and the subsequent release of lysosomes result in decreased production of adenosine triphosphate (ATP), which is the energy required for the survival of the helminth. • Due to diminished energy production, the parasite is immobilized and eventually dies. • The also have been shown to inhibit the enzyme fumarate reductase, which is helminth-specific. This enzyme is an essential component of the fermentation by which many parasites obtain their source of energy. • They also induce sterility in worms by inhibiting the egg production and uncoupling oxidative phosphorylation Anthelmintic spectrum • In ruminants, the benzimidazoles are most effective if deposited directly into the rumen. Administration directly into the abomasum, via the esophageal groove, may shorten the duration for drug absorption and increase the rate of excretion in the feces, which may reduce efficacy. Antinematodal effect • Broad spectrum of activity against roundworms (nematodes) • Larvicidal and ovicidal (Alb., Fenb., Feban., Oxf., Oxib.) effect • Triclabendazole has no activity against roundworms Anticestodal effect-Febantel, Fenbendazole, Netobimin, Albendazole, Mebendazole, Oxfendazole, Flubendazole Antitrematodal effect (for flukes, Fasciola, Dicrocoelium, Paramphistomum spp.) Netobimin, Albendazole, (only against adult stages of liver fluke) and Triclabendazole – only liver fluke (Fasciola hepatica) effective against both immature and adult flukes Pharmacokinetic features • Only limited amounts of any of the benzimidazoles are absorbed from the GI tract of the host (except e.g. Alb., Oxf., and Triclab.) • The limited absorption is probably related to the poor water solubility of these drugs. The little absorption that occurs is generally rapid, 2-7 hr after dosing with flubendazole and 6-30 hr after dosing with albendazole, fenbendazole, and oxfendazole, depending on the species. • 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.. • Absorption lasts for 6-30 h after dosing (Flub. 2-7 h). • Rate of passage is slowed by the rumen or cecum (equine).or reduced feed intake may increase the activity of BZs. • The rumen acts as a drug reservoir from which plasma concentrations can be sustained for long periods . ; it also slows the passage of unabsorbed drug through the GI tract.. • BZs are sparingly soluble in water, they are given PO as a suspension, paste, bolus or premix, (except Netobimin, which can be injected). Metabolism • of the benzimidazoles is variable and may alter their activity • Eg. Albendazole is rapidly and reversibly oxidized to its sulphoxide. Benzimidazole sulphoxides such as Oxfendazole and Albendazole sulphoxide bind poorly to parasite β-tubulin and probably act as prodrugs for Fenbendazole and Albendazole. - The sulphoxide may be irreversibly oxidized to its sulphone , which is significantly less active than the sulfoxide. • The biliary route is the most important pathway for secretion and (enterohepatic) recycling of BZs to the GI tract. • Both, the unabsorbed amount of BZs and bile excreted parent drugs and their metabolites are eliminated with faeces. Side-Effects - PO relative safe, non-toxic agents • Teratogenicity ( Rotational and flexural deformities and malformations of the limbs, carpal joints) with most Albendazole, Parbendazole and Cambendazole Fenbendazole is the safest anthelmintic in pregnancy . No teratogenic effects were noticed with mebendazole, fenbendazoole, oxibendazole, thiophanate • Hepatotoxicity (thiabendazole, oxibendazole, mebendazole). • Neurotoxicity - Resistance may occur (GI-roundworms in ruminants), frequently multiply resistance against BZs, - - Thiabendazole is applied topically (as fungicide, or against cutaneous larva migrans), has got anti-inflammatory action also. • • - Withholding periods are between 8-14 days before slaughtering for meat, and 3-5 days before milking , but are longer for bolus formulations Albendazole Albendazole, a broad-spectrum oral benzimidazole anthelmintic, is the drug of choice for treatment of hydatid disease and cysticercosis. It is also a major drug for the treatment of pinworm infection, ascariasis, trichuriasis, strongyloidiasis, and infections with both hookworm species Anthelmintic Actions: • Albendazole and its metabolite albendazole sulfoxide are thought to act by inhibiting microtubule synthesis in nematodes, thus irreversibly impairing glucose uptake. As a result, intestinal parasites are immobilized or die slowly, and their clearance from the gastrointestinal tract may not be complete until several days after treatment. • The drug also has larvicidal effects in hydatid disease, cysticercosis, ascariasis, and hookworm infection and ovicidal effects in ascariasis, ancylostomiasis, and trichuriasis. • The drug, is teratogenic and embryotoxic , is contraindicated in first trimester of pregnancy • Albendazole is administered on an empty stomach when used against intraluminal parasites but with a fatty meal when used against tissue parasites. • Mild and transient epigastric distress, diarrhea, headache, nausea, dizziness, lassitude, and insomnia are the adverse effects 2. IMIDAZOTHIAZOLES • Tetramisole, a racemic mixture (unsafe, recently not used) • Levamisole, L-isomer form • Butamisole HCl Mechanism Of Action • As agonists at excitatory nicotinic acetylcholine receptors of nematodes they are ganglion-stimulant (cholinomimetic) - They stimulate ganglion-like structures in somatic muscle cells of nematodes. This stimulation first results in sustained muscle contractions, followed by a neuromuscular depolarizing blockade resulting in spastic muscle paralysis due to prolonged activation of the nicotinic acetylcholine (nACh) receptors Anthelmintic spectrum • Antinematodal with broad spectrum of activity- adulticidal, larvacidal (including . Dirofilaria . immitis) , are not ovicidal • Effective against ascarids, strongyles, whipworms, and hookworms • No activity against flukes and tapeworms. • Resistance to levamisole has been reported for nematodes of cattle (not serious). • Nematodes resistant to Levamisole are cross resistant to Morantel (similar mode of action). • Levamisole is an anthelmintic with Immunomodulatory properties (Immunostimulant) • It enhances the immune responses by modifying the activities of Tlymohocyteds and phagocytes in immunologically depressed/ chronically ill animals • Immunimodulatory dose is 1/3 rd of anthelmintic dose given intermittently for three days Pharmacokinetic features The absorption and excretion of levamisole is rapid and not affected by the route of administration or ruminal bypass because it is highly soluble. In cattle, peak blood of levels <1 hr after SC administration • Concentrations decline rapidly; 90% of the total dose is excreted in 24 h., largely in the urine. • Withholding periods for meat are short, and frequently there is no or only a short, withholding period for milk. Side-effects • The safety index (SI) is narrow for Levamisole (SI = 4-6). • Cats, Horses, and certain dog breeds (e.g. Kuvasz) are very sensitive. • Toxic signs are: cholinergic-type signs of salivation, muscle tremors, ataxia, urination, defecation, and collapse, asphyxia due to respiratory failure. /Antidote: Atropine/ • Some transient inflammation at the site of SC injection. • Contraindications: - Not indicated in lactating cattle Dose: Ruminants, Swine, 5-7.5; Dogs 5; Poultry 10 mg/kg B.W. Normally is administered PO or SC, and efficacy is generally considered equivalent with either route. Immuniostimulant dose is 1/3rd(2.5mg/kg;SC) of anthelmintic dose . Topical preparations (pour on) for cattle have been developed. 3. TETRAHYDROPYRIMIDINES • Pyrantel Citrate, Tartrate salt: Cattle, Horses, Cats, Dogs, and Pigs • Pyrantel Pamoate /Embonate/ salt: Horses and Dogs (Cats) • Morantel citrate (The methyl ester analogue of pyrantel): Ruminants • Oxantel Mechanism of action • It is a depolarizing neuromuscular blocking agent in nematodal parasite • Irreversible Cholinomimetic activity, inducing contracture of the musculature similar to the contraction induced by ACh, , leading to spastic paralysis. • The action of Pyrantel can be antagonized by piperazine, which induces nematodal muscle relaxation Anthelmintic Spectrum • Antinematodal effect (Relatively large spectrum against GI nematodes – the first broad spectrum agents for against this parasites) . • Adult gut worms and larval stages that dwell in the lumen or on the mucosal surface. • Limited or no activity against migrating larvae, and Trichuris spp. • Nematodes resistant to levamisole are cross-resistant to morantel due to the similarities of their mechanisms of action. • Safer in young puppies, pregnant and lactating animals • Pharmacokinetic features • Pyrantel tartrate (or citrate) is well absorbed by pigs and dogs, poorly by ruminants. • Administration with food delays passage through digestive tract, prolonging the contact time of the drug with the parasite, thereby increasing the efficacy. • The pamoate salt is poorly soluble in water; this offers the advantage of reduced absorption from the gut and allows the drug to reach and be effective against parasites in the large intestine, which makes it useful in horses and dogs. • Metabolism of pyrantel is rapid, and the metabolites are excreted rapidly in the urine (40% of the dose in dogs); some unchanged drug is excreted in the faeces (principally in ruminants). • Blood levels usually peak 4-6 hr after PO administration. • Morantel is absorbed rapidly from the upper small intestine of sheep and metabolized rapidly in the liver; ~17% of the initial dose is excreted in the urine as metabolites within 96 hr after dosing • withholding periods for meat and milk are short /frequently no for milk/ Side-effects • Cholinergic-types of signs. /Antidote: Atropine • Morantel in Ruminants tends to be safer and more effective than pyrantel. • Contraindications: severly debilitated animals, as the cholinergic pharmacological actions are more pronounced in these animals 4. PIPERAZINES • • Piperazine (phosphate, adipate, citrate, sulfate, tartrate, HCl) Diethylcarbamazine citrate (DEC) Mechanism of action • Block neuromuscular transmission in the parasite by hyperpolarizing the nerve membrane, which leads to flaccid paralysis, (reversible vermifuge effect, without killing them) • Also block succinate production by the worm. The parasites, paralyzed and depleted of energy, are expelled by peristalsis. • DEC disrupta the microtubule and inhibits the microtubule polymerisation in immature Dirofilaria immitis , filaria, microfilaria Anthelmintic Spectrum • The spectrum of activity of Piperazine is largely against ascarid parasites in all animal species. And Large doses against hookworms,pinworms and nodular worms. • Mature worms are more affected than larvae , and hence treatment may be repeated at 2 weeks intervalk in dogs and cats and at 4 week interval in ruminants • Diethylcarbamazine is used for heartworm prevention in dogs; however, its use is declining. In existing infections, the dogs must first be cleared of adult • • • heartworms and microfilariae to avoid reaction, then are given DEC daily PO throughout the mosquito season to prevent reinfection Diethylcarbamazine is a drug of choice in the treatment of filariasis, Wuchereria bancrofti, , Brugia timori, . Onchocerca volvulus loaloaiasis, and tropical eosinophilia. Diethylcarbamazine has shown in vivo and in vitro immunosuppressive actions, the mechanism of which is imperfectly understood. Has also been used to treat prepatent Dictyocaulus viviparous infections (lungworm infection) in cattle, (relatively ineffective against the adult worms). Pharmacokinetic features • Piperazine is rapidly absorbed from the GI tract,- Piperazine base can be detected in the urine as early as 30 min. after administration. • The excretion rate is maximal at 1-8 h, and excretion is practically complete within 24 h. • DEC is rapidly equilibrates with all tissues except fat. It is excreted, principally in the urine, as unchanged drug and the N-oxide metabolite. • Dosage may have to be reduced in patients with persistent urinary alkalosis or renal impairment. Side-effects • The safety margin is wide (less in horses, puppies and kittens) with no teratogenic effects • Toxicity caused by to large doses includes vomiting, diarrhoea and ataxia. • Adverse Reactions with DEC a.Drug-Induced Reactions: Reactions to diethylcarbamazine itself are mild and transient and start within 2-4 hours: headache, malaise, anorexia, and weakness are frequent; nausea, vomiting, dizziness, and sleepiness occur less often. The drug should be taken after meals. b. Reactions Induced by Dying Parasites: Adverse effects also occur as a result of the release of foreign proteins from dying microfilariae or adult worms in sensitized patients. Eosinophilia and leukocytosis are usually intensified. 5. ORGANOPHOSPHATES Originally pesticides • Dichlorvos (Horses, Pigs, Dogs, and Cats) • Cythioate (Dogs and Cats) • Trichlorfon (Horses and Dogs) • Naftalofos, Haloxon, Coumaphos, Crufomate (Ruminants) Mechanism of action • Irreversible acetyl cholinesterase(AChE) inhibition by phosphorylating their esterification sites, this blocks cholinergic nerve transmission in the parasite, which results in spastic paralysis. Anthelmintic Spectrum • Effective against GI-roundworms (and bots). Limited efficacy against immature stages. Ineffective against migrating larvae tapeworms and flukes. Pharmacokinetic features • Good absorption after oral administration, readily penetration through unbroken skin (high lipid solubility). • Inactivation by the liver. • Excretion mainly with urine; to a lesser extent with milk. Side-Effects • Narrow margin of safety. • Signs of overdosing: restlessness, salivation, miosis, bradycardia, bronchial constriction, diarrhoea, ataxia, tremors. - Strict attention to dosage is necessary. • Topical formulations (sprays, collars, washes) can present significant hazards to young infants of small animals after ingestion, inhalation, or transcutaneous absorption. Basic liquids (soaps) inactivate them. • Contamination of the environment through faecal excretion. • Concurrent use of other cholinesterase-inhibiting drugs should be avoided. • Antidotes: Atropine and 2-PAM-type enzyme-reactivators. 6. SALICYLANILIDES AND SUBSTITUTED PHENOLS Salicylanilides • Brotianide, Rafoxanide Clioxanide, Closantel, Niclosamide, Oxyclozanide, • • Substituted phenols • Bithionol, , Dichlorophene Hexachlorophene, Niclofolan, Menichlopholan, Nitroxynil, Disophenol and Diamphenethide (is an aromatic amide) Nitroscanate (only in dogs) Mechanism Of Action • Uncoupling of oxidative phosphorylation processes • These compounds act as protonophores, allowing hydrogen ions to leak through the inner mitochondrial membrane. Anthelmintic Spectrum • They are used in sheep and cattle extensively against fasciolosis and haemonchosis* (hematophagous nematodes, e.g. Haemonchus* and Bunostomum). • Lowered efficacy of a number of the salicylanilides and substituted phenols against immature flukes may be due to the high protein binding of these drugs in the blood. • Diamfenetide (diamphenethide) is unique , having high activity against the youngest immature stages, a diminution of activity as the flukes mature., thus effective in acute fascioliasis • They are generally ineffective against nematodes (due to a lack of drug uptake). • Nitroscanate, Dichlorophen, and Nicliosamide are active against tapeworms (Taenia spp., the first two drugs against Dipylidium, little or variable efficacy against Echinococcus spp.) Closantel is a endecticide, can be given both orally and parenterally (SC route) Oxyclozanide is effective against nasal schistosomiasis and adult liver flukes Rafoxanide is effective against nematodes, flukes, and tissue invading fly maggots Pharmacokinetic Features • The fasciolicidal effects of salicylanilides (such as rafoxanide) in sheep depend on persistence of the drug in plasma, which influences their transport throughout the body and rate of elimination. • Closantel, rafoxanide, and oxyclozanide have long terminal half-livesin sheep (14.5, 16.6, and 6.4 days, respectively), which are related to the high plasmaprotein binding (>99%) of these 3 drugs. • Secretion via the liver and bile is important for drugs active against adult Fasciola spp., concentrations of fasciolocides and their metabolites are higher in faeces than in urine. • Residues in liver are detectable for weeks after administration., thus the need for longer withholding periods. • Oxyclozanide also is bound to plasma protein and then metabolized in the liver to the anthelmintically active glucuronide and excreted in high concentration in the bile duct, where it encounters the mature flukes. • Diamfenetide is metabolized in the gut, and to a greater extent in the liver, to an active metabolite that can enter hepatic cells and exert its antiparasitic effect against very young stages of the fluke. • Because rumen bacteria metabolize and destroy the activity of nitroxynil, it must be injected. • Nitroscanate is used in small animals against Toxocara , Toxascaris , Taenia , Dipylidium , Ancylostoma , Uncinaria , and Echinococcus spp . Vomiting occasionally occurs after treatment Side-Effects • General uncouplers of oxidative phosphorylation, their side effects are lower than those of many other anthelmintic agent. • Mild anorexia and unformed faeces may be seen after treatment at recommended dosages. • High dosages may cause blindness, hyperthermia, convulsions, and death— classic signs of uncoupled phosphorylation. • Adverse effects are most commonly seen in animals that are severely stressed, in poor condition nutritionally or metabolically, or that have severe parasitic infections. 7. MACROCYCLIC LACTONES (AVERMECTINS AND MILBEMYCINS) (Macrolide enedecticides) Avermectins : Abamectin, Doramectin, Eprinomectin, Ivermectin, and Selamectin Milbemycins: Moxidectin, Nemadectin, Milbemycin oxime, MilbemycinD Avermectins • • • • • • These agents are potent ectoparasiticides as well , called as endectocides Structurally similar to macrolide group of antibacterials Semi-natural fermentation products of Steptomyces avermitilis and cyanogriseus. Milbemycins: • Structurally slightly differ from avermectins, mainliy in the absenc of disachharide group on C-13 • Moxidectin is derived semisynthetically, from the fermentation metabolite of nemadectin, milbemycin being derived from Streptomyces hygroscopicus • Highly lipophilic drugs, soluble in organic solvents and insoluble in water, the residue concentrations found n fat tissues being ten times higher than those reported for avermectins Mechanism Of Action • They act by GABA potentiation- potentiate the release of GABA (inhibitory neurotransmitter) and activation of GABA gated chloride channels and glutamate gated chloride channels (specific to parasites) at the excitatory motor neurons (in nematodes) and myoneural junction (in arthropods) • This causes the channel to open, allowing an influx of chloride ions. • Cl- influx lowers cell membrane resistance and causes a slight hyperpolarisation of the resting potential of post synaptic cells. • As a result, neurotrsansmission of stimuli to the muscle is prevented , followed by flaccid paralysis, subsequent death and expulsion. • Mammalian GABA mediated transmission is limited to CNS and these agents do not cross Blood brain barrier(except in collie breed dogs and Murray grey cattle, some Australian shepherds due to genetic predisposition ) and hence have wide margin of safety in mammals. • Avermectins also interfere with reproduction of the partasites resulting in reduced oviposition in ticks and abnormal egg laying in nematodes, sterility in both male and female filarial nematodes Anthelmintic Spectrum • Active against both endo and ectoparasites- Endectocidal Active against all stages of nematodes(hypobiotic larvae) including GI nematodes(Ascaris, Strongylus, Ostertagia, Haemonchus spp, etc), lung nematodes( Dictyocalus filaria, Metastrongylus spp), eye worms( Thelazia spp.) • Active against only the microfilarial stagees (immature heart worm) of many filaroids, ineffective against adult filarial worms. It is not known whether this stage differentiation is caused by the failure of the drug to reach the site of action or the innate mechanistic insensitivity of the adult parasites • Active against schistosomes and ectoparasites (arthropods).- tick, flea. mite, horn flies, warbles, maggot fly bots • No activity against cestodes and trematodes as they lack the GABA mediated neurotransmission • Resistance may occur (parallel with BZs and levamisole). Doramectin: • Novel avermectin produced by mutational biosynthesis - Broad range of activity against GI nematodes, lung worms, eyeworms, sucking lice, grubs, ticks, mites and screw worms in cattle. - Efficacy against the myiasis is unique among the macrocyclic lactones Can be administered SC and IM - Other features being similar to ivermectin Pharmacokinetic Features of avermectins and milbemycins • Lipophilic compounds, good absorption, wide distribution. • Regardless of their route of administration, macrocyclic lactones are distributed throughout the body and concentrate in adipose tissue. While 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 prolongs the residence of drug in the peripheral plasma. • Accumulation in fatty tissue, long lasting effect, residues. • In ruminants, the macrocyclic lactones are, like benzimidazoles, most effective if deposited directly into the rumen • Concentrations of ivermectin are high in digesta sampled from the distal intestine, indicating that biliary secretion is an important pathway for clearance of macrocyclic lactones. This pathway also has been conclusively demonstrated for clearance of benzimidazole compounds. • The extended high concentration in bile is influenced by prolonged exchange of drug from lipid reserves and the enterohepatic recycling of biliary compounds through the portal and biliary pools. • The macrocyclic lactones are mostly excreted in the feces, the remainder (<10%) in the urine. • Most macrocyclic lactones are also excreted in milk. • No embryotoxic/teratogenic effects, safe for use in breeding and pregnant animals Adverse/ Side-Effects • The safety index for the macrocyclic lactones is typically wide , but Abamectin and Moxidectin are contraindicated in calves and foals <4 mo old. • Mammalian safety appears to depend on p-glycoprotein activity in the bloodbrain barrier. , though horses are sensitive to some extent. Transcient pruritus, cutanoeous oedema may occur in horses following oral or IM treatment, attributed to death of the microfilariae. • Cattle breeds (Murray Grey) and purebred and crossbred Collies are most sensitive for ivermectin toxicity • Moxidectin injectable can be used in ivermectin sensitive collies Toxicity signs: Nervous signs (idiosyncratic reactions) including ataxia, depression, muscle weakness, blindness, coma, and death were observed, especially in Collies. • Physostigmine, with supportive fluid therapy helps in countering the milder form of toxicity signs • Milbemycin oxime has greater margin of safety in ivermectin sensitive collies and in microfilaremic dogs - Problem of environmental burden/hazard: The avermectins are largely excreted in feces and they bind to the soil and suppress the larvae(breeding) of some the soil / dung degrading Diptera insects (dung beetle- Onthophagus gazella ) even up to 4 weeks following the treatment.. Thus the residue concentration of avermectins persist for a longer time( several weeks) in the pasture soil grazed by the treated animals, before getting slowly degraded. Application Ivermectin and doramectin-1% injectable, 10 mg tablets, 1% pour on • SC- injection- Ruminants 0.2 (200µg/kg, strict SC), Swine 0.3 mg/kg B.W. • PO- Swine premix, Horses paste, Dogs tablets • Dermal- (spot on, pour on) 0.6-0.8 mg/kg B.W. Milbemycins: Moxidectin – 1% injectable, , 0.1% . oral drenchs , 0.5% pour on solution, 7.5, 15, 30 µg tablets ( oral and Inj Dose-200µg/kg, Pour on - 500µg/kg) Milbemycin oxime-5,7.5mg,11.5,23mgtablets,(dose- 0.5- 0.99mg/kgdog; 2mg/kg-cats) ; recently has been combined with Lufenuron in a tablet formulation for the simultaneous prevention and control of flea infestations and nematodes Treatment of Heartworm Disease Heartworm disease is caused by the filarial nematode Dirofilaria immitis • Three stages of management of heartworm disease – Preventing third-stage larvae from reaching maturity (preventative) – Adulticide therapy – Eradication of circulating microfilariae after infection • Preventing third-stage larvae from reaching maturity (preventative) – Daily oral preventative • Diethylcarbamazine (DEC) – Given during mosquito season and two months after – Patient must be heartworm negative – Once-monthly oral preventatives • Ivermectin • Milbemycin – Once-monthly topical preventative • Selamectin – Six-month injectable preventative • Moxidectin • Adulticide therapy – Melarsomine • Given in the epaxial muscles • Less toxic than former drug (thiacetarsamide) • Side effects include nephrotoxicity and hepatotoxicity • Eradication of circulating microfilariae after infection – Ivermectin (given at higher dose as a microfilaricide) – Milbemycin – Levamisole (infrequently used) Heart worm adulticides(Anti nematodals) : are organic arsenical compounds 1. Thiacetarsamide sodium Administered IV, (2.2mg/kg) ,irritant to tissues; avoiding extravasation • Hepatotoxic and nephrotoxic • Arsenic toxicity menifestated as persistent vomition, icterus, orange coloured urine ; can be treated with Dimercaprol(BAL; 8.8mg/kg/day in 4 divided doses) 2. Melarsomine • • • Dihyrochloride salt , reconstituted with 0.9% normal saline (2.5mg/kg;IM) Localized oedema, distress, restlessness, salivation, tachycardia- toxicity signs are similarly treated as above. 8 MISCELLANEOUS/OTHERS ANTHELMINTICS (ANTI NEMATODALS) PHENOTHIAZINE • Sterilizes the worms by inhibiting egg production and destroying the hatched larvae • Not used nowadays(limited, only in swines), because of its metabolitephenothiazine sulfoxide, causing photosensitization resulting in corneal ulcers DISOPHENOL • Active aginst hook worms( Ancylostoma caninum) of canines • Acts by uncoupling the oxidative phosphorylation Highly irritant on SC injection, not used nowadays 9 . ISOQUINOLIN AND BENZAZEPIN DERIVATIVES ( Prazino isoquinolones ) Dealt under Anticestodal agents ANTI TREMATODAL AGENTS 1. HALOGENATED HYDROCARBONS Carbontetrachloride • • • Inhibits cholesterol syntheisis in host liver Accumulation of methyl sterols, (toxic to host also), taken up by flukes and subsequently get killed Potent hepatotoxic, use declined now 2. BISPHENOLIC COMPOUNDS Bithionol • It l is the drug of choice for the treatment of sheep fascioliasis (sheep liver fluke) • Bithionol is also an alternative drug in the treatment of pulmonary paragonimiasis. (lung fluke) • The mode of action of bithionol against Paragonimus westermani has not been established. • Hexachlorophene is the other agent 3. SALICYLANILIDES Closantel, Resorantel Rafoxanide Ciloxanide Oxyclozanide Brotaianide Diamphenethide are the commonly used ones • Highly effective against adult rumen flukes (Amphistomes and Paramphistomes) and tissue flukes • The reason for mature flukes benig more vulnerable, than immature flukes to most of the fasciolicides: Immature flukes in the liver parenchyma ingest mainly liver cells, which contain little anthelmintic; plasma-protein binding limits entry of the drug into the tissue cells. As the flukes grow and migrate through the liver, they cause extensive hemorrhaging and come into contact with anthelmintic bound to plasma protein. When they reach the bile ducts, they are in the main excretory hannels for the active metabolites of the fasciolicides and are exposed to toxic concentrations. • Diamphenethide is metabolized in the gut, and to a greater extent in the liver, to an active metabolite that can enter hepatic cells and exert its antiparasitic effect against very young stages of the fluke. , the mechanism of action being similar to praziquantel causing vacoulation and death 4. SUBSTITUTED (NITRO) PHENOLS Niclofolan , Nitroxynil, Disophenol 5 BENZIMIDAZOLES • Netobimin, Albendazole, (only against adult stages of liver fluke, Fasciola, Dicrocoelium, Paramphistomum spp.) Triclabendazole – active only against liver fluke (Fasciola hepatica) and effective against both immature and adult flukes 6 CLORSULON • • • • Aminobenzene disulphonamide derivative Clorsulon is a sulfonamide given PO as a suspension for infections with (mainly) adult liver flukes in sheep and cattle and as a SC injection for cattle, in combination with ivermectin In plasma, clorsulon is bound to protein and, when ingested by liver flukes, inhibits enzymes of the glycolytic pathway in liver flukes. (cellular energy production is disrupted). Although its safety margin is wide, clorsulon is not licensed for use in lactating dairy cows producing milk for human consumption • • 7. EMETINE HYDROCHLORIDE Emetine and dehydroemetine (less toxic than emetine) are alternative drugs for the treatment of Fasciola hepatica infection. Both drugs are sometimes effective but are more toxic than triclabendazole or bithionol (the drugs of choice). ANTI CESTODAL AGENTS 1. ISOQUINOLIN AND BENZAZEPIN DERIVATIVES ( Prazino isoquinolones ) • • Praziquantel and Epsiprantel (closely related analogs) Most widely used and safest Anticestodal- praziquantel HCl Mechanism of action • Induction of spastic paralysis in the parasite., the drug increases cell membrane permeability to calcium, resulting in vacuolization, marked contraction, paralysis, dislodgement, and death • • • Primarily action is on neuromuscular coordination, by interfering with the regulation of intracellular Ca2+ concentrations, impairing both motility and function of the suckers of the cestode. In schistosome infections of experimental animals, praziquantel is effective against adult worms and immature stages; adult worms are rapidly immobilized and then passively shift to the liver. In addition, when a single high dose of praziquantel is given concurrently with an infecting dose of cercariae, all immature forms are killed; thus, praziquantel has a prophylactic effect. Anthelmintic spectrum • Anticestodal effect (against tapeworms). -- High efficacy against mature and larval cestode parasites including Echinococcus spp (Hydatid disease). and against certain trematodes (blood flukes). • Praziquantel is effective in the treatment of schistosome infections of all species and most other trematode and cestode infections, including cysticercosis • Not effective against nematodes and liver flukes ( Fasciola hepatica) • Epsiprantel is effective against Taenia and Dipylidium, but not Echinococcus Pharmacokinetic features • Rapid and almost complete absorption from the GI • Distribution to all organs (reenter gut lumen via bile and mucosa) • Rapid hydroxylation into inactive forms in the liver and secretion in bile. Side-Effects • Wide safety margin, practically non-toxic. • • • • • 2. NICLOSAMIDE salicylanilide derivative. It is minimally absorbed from the gastrointestinal tract: neither the drug nor its metabolites have been recovered from the blood or urine. Following oral administration in animals and humans, no hematologic, renal, or hepatic abnormalities have been noted. Scoleces and segments of cestodes, but not ova are rapidly killed on contact with niclosamide The drug interferes a) with energy metabolism and reduce glucose uptake b) depletes glycogen stores in worms c) interferes with mitochondrial action of cestodes and uncouples/ inhibition of oxidative phosphorylation or to its ATPase- over stimulating property leading to energy deficiency and the death.. With the death of the parasite, digestion of scoleces and segments begins. • • • Safer in pregnant and debilitating animals Indicated in dog, cat tapeworms and sheep Moneziasis Adverse Reactions : infrequent, mild, and transitory. Nausea, vomiting, diarrhea, and abdominal discomfort 3. DICHLOROPHEN MOA and Indications similar to niclosamide 4. RESORANTEL Inhibits glucose degradation pathway and terminal stages of glucose pathway 5. NITAZOXANIDE Nitazoxanide, a pyruvate ferredoxin oxidoreductase inhibitor, acts against a broad spectrum of protozoa and helminths that occur in the intestinal tract It is currently used for the treatment of protozoal infections. The site of action of this compound has not been established in nematodes although anaerobic electron transport enzymes may be a potential target The efficacy of this compound is relatively low compared to other anticestodal agents. 6. BUNAMIDINE (HCl, hydroxynapthoate salts) • • • • • Naphtamidine compound. Used in small animals, leads to digestion of tapeworms in the gut of the host, due to an inhibition of glucose uptake of worms. Most effective if given after fasting. It is absorbed and metabolized in the liver., Hepatotoxic_ not given routinely Vomiting and mild diarrhoea may be seen, and exercise or excitement should be avoided in dogs soon after administration. 8. NATURAL ORGANIC COMPOUNDS Plant origin Possibility of recovery of worm Given in combination with purgative Worms are paralysed and eliminated Low efficacy of the compounds • • • • • Arecholine • Areca catechu derived alkaloid Nicotine • Nicotiana tabaccum Cucurbitine • Pumpkin (Cucurbita pepo) seeds Kamala • Mallotus phillippinensis glands of fruits – for cat tapeworm Filicic acid • Dryopteres filiximas dried rhizome 9. INORGANIC COMPOUNDS Tin oxide and Lead arsenate are highly toxic with low margin of safety, have been discontinued 10. BENZIMIDAZOLES - Fenbendazole ,Albendazole, Mebendazole and oxfendazole NEWER ANTHELMINTICS Due to the development of drug resistance, there is a continual need for newer anthelmintics with novel and different mode of action 1. EMODEPSIDE (CYCLODEPSIPEPTIDES) Newer anticestodal and antinematodal, novel mode of action The cyclo octa depsipeptide molecule, emodepside, is a semi-synthetic derivative of a fermentation product obtained from the fungus, Mycelia sterilia, (Camelia japonica) . It is effective against isolates of parasites that are resistant to benzimidazole, levamisole and ivermectin The molecule has pore-forming properties in planar lipids, which does not appear to be important in conferring its anthelmintic potency as an optical isomer of emodepside, with similar pore forming properties, does not have anthelmintic action. It may act through stereospecific binding to a receptor, latrophilin which has homology to mammalian latrophilins, a class of G protein-coupled receptors which bind the neurotoxin, latrotoxin. Latrotoxin paralyses mammals by triggering neurotransmitter release. Emodepside may cause paralysis of nematodes by stimulating excessive neurotransmitter release at neuromuscular sites. ( NOTE: The pharmacology and details of these newer anticestodal agents : DESASPIDIN , FLUXANE and MARNATOL ; which I could not find in many of the articles or books so far. Any information with regard to these agents may kindly be uploaded in scribd or may be sent to my mail ID:
[email protected] )