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Transcript
Anthelminthic drugs Gábor Pozsgai Pharmacology and Pharmacotherapy University of Pécs 2013 Introduction • Selective toxicity – eukaryoitic organisms – multicellular organisms • Life cycle might involve insect or other animal vectors/hosts Introduction • Drug targets – neuromuscular junctions • GABAergic transmission, too – microtubules – DNS – tegument – metabolic pathways • fumarate reductase • oxidative phosphorylation • arachidonic acid metabolism – adenosine uptake Nematodes (roundworms) • • • • • • • • • • Enterobius vermicularis Trichuris trichuria Ascaris lumbricoides Toxocara canis Visceral larva migrans Necator americanus Ancylostoma duodenale Strongyloides stercoralis Cutan larva migrans Trichinella spiralis helmiths hatch from eggs within hours in the soil more maturing is needed in the soil geohelminths larvae hatch from eggs in the soil that can penetrate human skin Nematodes (roundworms) • Filariae – lymphatic filariasis • Wuchereria bancrofti • Brugia malayi • Brugia timori – subcutaneous filariasis • Loa loa, eyeworm • Onchocerca volvulus, river blindness • Mansonella streptocerca – serous cavity filariasis • Mansonella perstans • Mansonella ozzardi Trematodes (flukes) • Schistosoma haematobium • Schistosoma mansoni • Schistosoma japonicum • Clonorchis sinensis • Fasciola hepatica lives in bladder veins intestinal schistosomiasis live in bile vessels Cestodes (tapeworms) • • • • Diphyllobotrium latum Hymenolepis nana Taenia saginata Taenia solium • Echinococcus granulosus • Echinococcus multilocularis might cause human cysticercosis final hosts are dogs, foxes humans are intermediate hosts Treatment of nematodal infections • Benzimidazole derivatives – selectively bind to β-tubulin of the parasites – inhibit polymerisation • disrupt motility, DNA replication – inhibit glucose uptake • degeneration of tegumental and intestinal cells – damage of the tegument of the protoscolex in tapeworms – inhibit mitochondrial fumarate reductase – inhibit oxidative phosphorylation Treatment of nematodal infections • Benzimidazole derivatives – resistance • lower affinity due to mutation • lower expression of β-tubulin – very lipophilic, almost insoluble in water – absorption is increased by fatty meals – strong plasma protein binding – teratogenic Treatment of nematodal infections • Benzimidazole derivatives – all drugs of the group • • • • • • Ascaris lumbricolides Enterobius vermicularis Necator americanus Ancylostoma duodenale Trichuris trichuria Trichinella spiralis (intestinal forms only) – albendazole • Strongyloides stercoralis • Echinococcus granulosus • neurocysticercosis Treatment of nematodal infections • Benzimidazole derivatives – albendazole • increased liver enzymes • neutropenia – mebendazole • • • • • • low absorption strong plasma protein binding nausea, vomiting headache, dizziness reversible hair loss neutropenia Treatment of nematodal infections • Benzimidazole derivatives – tiabendazole • antipyretic, antifungal, anti-inflammatory, immunomodulatory, scabicidal effect • ditributed in the skin • side effects are more frequent Treatment of nematodal infections • Benzimidazole derivatives – tiabendazole • neuropsychiatric symptoms, dizziness, visual and hearing disturbances • nausea, vomiting • itch • bradycardia, hypotension • elevated liver enzymes • allergic reaction against dying worms Treatment of nematodal infections • Benzimidazole derivatives – triclabendazole • veterinary use • exceptional chemical structure (lacks carbamate group) • also for Fasciola hepatica, ectoparasites – ciclobendazole – flubendazole – fenbendazole • veterinary use • the latter caused abortions, myelodepression, GIT side effects Treatment of nematodal infections • Pyrantel embonate/pamoate, oxantel – tetrahydropyrimidine derivative – nicotinic receptor agonist, cholinesterase inhibitor – induces spastic paralysis of the parasites – only active against parasites in the GIT lumen – low absorption – systemic neuromuscular blockade Treatment of nematodal infections • Pyrantel embonate/pamoate, oxantel – dizziness, fatigue, fever – nausea, vomiting – rash – should not be used during pregnancy, breastfeeding and in children below 2 years of age Treatment of nematodal infections • Piperazine – GABA receptor agonist • flaccid paralysis – selectively damages pacemaker cells of the parasites – only active against Ascaris and Enterobius – seizures • contraindicated in epilepsy patients Treatment of nematodal infections • Diethylcarbamazine – active against Wuchereria, Loa, Brugia malayi – piperazine derivative used in filariasis patients – stimulates innate immunity – paralysis and damaged tegument – inhibits microtubule polymerisation – inhibits arachidonic acid metabolism Treatment of nematodal infections • Diethylcarbamazine – kills both microfilariae and adult worms – better excreted in acidic urine – headache, nausea – Mazzotti reaction • gradually increased dose • glucocorticoids Treatment of nematodal infections • Ivermectin – – – – avermectin derivative (avermectine B1a and B1b) semisynthetic macrocyclic lactone from Streptomyces active in filariasis, especially Onchocerca also active against cutan larva migrans, Strongyloides, scabies – activation/positive modulation of glutamate-gated Clchannels • pharyngeal paralysis – induces GABA release, activates GABA receptors, enhances the binding of GABA to its receptors • tonic paralysis Treatment of nematodal infections • Ivermectin – – – – only kills microfilariae, does not affect adult worms kills microfilariae in utero, too has to be taken every 6 months for 10-15 years resistance has occured already • P-glycoprotein – does not cross the blood-brain-barrier, slowly enters the eyes – Mazzotti reaction – contraindicated in case of damaged blood-brainbarrier, pregnancy, below 5 years of age Treatment of nematodal infections • Doxycycline – Onchocerca volvulus contains obligate symbiont endobacteria, the Wolbachia – treating these with doxycycline damages fertility, embryogenesis and viability of the parasite Treatment of nematodal infections • Levamisol – – – – – – – – imidazothiazole derivative depolarizing muscle relaxant inhibits fumarate reductase only active against Ascaris well absorbed and distributed, enters the CNS disulfiram effect agranulocytosis immunomodulator • with 5-fluorouracil for colonic cancer, melanoma, head tumours – used for the dilution of illegal cocaine Treatment of nematodal infections • Bephenium hydroxynaphthoate/embonate – depolarizing muscle relaxant – quaternary amine, low absorption – only active against Ascaris, Ancylostoma, Necator – might excite mammalian autonomous ganglia – dizziness – nausea, vomiting, diarrhoea Treatment of nematodal infections • Pyrvinium embonate – inhibits gucose absorption • worms die of starvation – only active against Enterobius, but not against eggs – not absorbed in human – red discoloration of the feces – GIT side effects – itch, allergy – should be used with care during pregnancy, breastfeeding, below 3 months of age Treatment of trematodal infections • Praziquantel – quinoline derivative – Schistosoma, other trematodes, cestodes, neurocysticercosis – increased permeability to Ca2+ of parasite membranes • tonic paralysis – inhibits uptake of adenosine – high doses damage the tegument Treatment of trematodal infections • Praziquantel – good absorption, enters the CNS – strong plasma protein binding – high first pass metabolism – abdominal pain, nausea, vomiting – headache, dizziness, confusion, fatigue – itch – seizures in case of neurocysticercosis – contraindicated in cysticercosis of the eyes, during pregnancy and breastfeeding Treatment of trematodal infections • Oxamniquine – quinoline derivative – binds parasite DNA • inhibits nucleic acid synthesis – anticholinergic effect – only active against Schistosoma mansoni, mainly males • worms detach from mesenteric veins and are shifted to the liver • females return to the mesenteric veins, but cannot lay eggs – – – – headache might trigger seizures in epileptic patients orange discloloration of the urine allergic reaction against dying parasites Treatment of trematodal infections • Metrifonate – prodrug, activated non-enzymatically • the active metabolite is dichlorvinyl dimethylphosphate (dichlorvos, DDVP), a cholinesterase inhibitor • fast inactivated in the plasma • depolarizing muscle relaxant – paralysed worms are transported from bladder veins into the lung, where they die – only active against Schistosoma haematobium, but not eggs – abdominal pain – interactions with peripheral muscle relaxants and organophosphates have to be minded Treatment of trematodal infections • Bithionol – for the treatment of Fasciola hepatica and other veterinary tapeworm infections – impairs the function of parasite neuromuscular junctions – inhibits egg formation – damages the tegument – inhibits succinate oxidation – inhibits oxidative phosphorylation – chelates iron Treatment of trematodal infections • Bithionol – very lipophilic, low absorption, high concentration in the bile – abdominal cramps, diarrhoea, nausea, vomiting – rash, photosensitivity – toxic hepatitis, leukopenia • regular liver tests and blood counts are necessary Treatment of trematodal infections • Niridazole – active against Schistosoma species – inhibits phosphofructokinase • the worms are shifted to the liver – inhibits oogenesis, spermatogenesis of the parasites – potentially mutagenic, carcinogenic – antispermatogenic effect has been reported in humans – might cuase neuropsychiatric symptoms Treatment of trematodal infections • Stibophen – antimony containing compound • binds sulfhydryl groups of enzymes and other proteins – active against Schistosoma species – inhibits phosphofructokinase • paralysis and hepatic shift of the worms – shock, TTP, hemolytic anemia Treatment of cestodal infections • Niclosamide – active against all tapeworms, but only against intestinal forms • in case of Taenia solium laxatives are recommended after treatment – inhibits glucose uptake, enhances glycolysis and inhibits the citrate cycle • lactic acidosis • worms are no longer protected against digestive enzymes – – – – uncoupling effect low absorption abdominal pain, nausea, vomiting should not be used in the 1st trimester of pregnancy Treatment of cestodal infections • Dichlorophen – active against Taenia solium, Taenia saginata and Diphyllobotrium latum – strong laxative effect – photosensitivity, rash – abdominal pain, diarrhoea, nausea Helminth(s) Drug(s) used Threadworm (pinworm) Enterobius vermicularis Strongyloides stercoralis (threadworm in the USA) Mebendazole, albendazole, piperazine Albendazole, ivermectin Common roundworm Ascaris lumbricoides Levamisole, mebendazole, piperazine Other roundworm (filariae) Wuchereria bancrofti, Loa loa Onchocerca volvulus Guinea worm (Dracunculus medinensis) Trichiniasis (Trichinella spiralis) Cysticercosis (infection with larval Taenia solium) Tapeworm (Taenia saginata, Taenia solium) Hydatid disease (Echinococcus granulosus) Hookworm (Ankylostoma duodenale, Necator americanus) Whipworm (Trichuris trichiura) Diethylcarbamazine, ivermectin Ivermectin Praziquantel, mebendazole Tiabendazole, mebendazole Praziquantel, albendazole Praziquantel, niclosamide Albendazole Mebendazole, albendazole Mebendazole, albendazole, diethylcarbamazine Blood flukes (Schistosoma spp.) S. haematobium S. mansoni S. japonicum Praziquantel Praziquantel Praziquantel Cutaneous larva migrans Ankylostoma caninum Albendazole, ivermectin, tiabendazole Visceral larva migrans Toxocara canis Albendazole, tiabendazole, diethylcarbamazine British National Formulary 2008.
