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Chemotherapy of Helminthic Infections - Anti-helminthic Drugs PowerPoint Presentation

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Description : Helminths (worms) are multicellular organisms that infect very large numbers of humans and cause a broad range of diseases. Learn about the types of helminthic infections, i.e., Roundworms (Nematodes), Flukes (Trematodes) and Tapeworms (Cestodes).

Tags : Chemotherapy of Helminthic Infections, Anti-helminthic Drugs, Helminths

Published on : Nov 06, 2020 | Views : 3271 | Downloads : 6

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Chemotherapy of Helminthic Infections (Anti-helminthic Drugs) Dr. Mohammed Samir Hussein BCs of Pharmaceutical Science MD of Clinical Pharmacology
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Learning Outcomes Types of worm infections (Helminths) Types/Classification of Anti-helminths drugs Mechanism of action Toxicity Clinical uses Contraindications Drug Interactions Resistance
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Helminthic infections Helminths (worms) are multicellular organisms that infect very large numbers of humans and cause a broad range of diseases Types of helminthic infections Roundworms (Nematodes) - Ascaris lumbricoides Flukes (Trematodes) - Schistosoma japonicum Tapeworms (Cestodes) - Taenia saginata Taenia saginata Schistosoma japonicum Ascaris lumbricoides Roundworm Flukes Tapeworm
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Helminths: The Basic Facts
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Classification of Helminths
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Neuromuscular Junction Nicotinic-acetylcholine receptors GABA & Cl ion channel Microtubule Glucose uptake Metabolism ATPase activity Oxidative Phosphorylation Calcium homeostasis Calcium ion channel Integumentary system B-tubulin and polymerization Immune system Drugs targets of worms
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BENZIMIDAZOLES The principal groups of anthelminthics used clinically Mebendazole, Tiabendazole and Albendazole. Inhibiting the polymerisation of helminth β-tubulin, Thus interfering with microtubule-dependent functions such as glucose uptake. Cure rates are generally between 60% and 100% with most parasites
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ALBENDAZOLE Albendazole is a benzimidazole carbamate a broad-spectrum oral anthelminthic It rapidly undergoes first-pass metabolism in the liver The active metabolite albendazole sulfoxide Absorption may be increased by food, especially fats MOA: It inhibits microtubule synthesis of helminths It has larvicidal effects hydatid disease, ascariasis Ovicidal effects in ascariasis It is administered on an empty stomach when used against intraluminal parasites but with a fatty meal when used against tissue parasites
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Clinical Uses: Hydatid Disease Dosing is 400 mg twice daily with meals for 1 month or longer Neurocysticercosis 400 mg twice a day for up to 21 days. Ascariasis single dose of 400 mg orally (> 2 years age) Trichuriasis three daily 400-mg oral doses Hookworm and Pinworm Neurocysticercosis Trichuriasis Ascariasis ALBENDAZOLE
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Adverse Reactions, Contraindications, & Cautions: Nearly free of significant adverse effects Mild and transient epigastric distress, diarrhea Abdominal distress Blood counts and liver function studies should be monitored during long-term therapy The drug should not be given to patients with known hypersensitivity to other benzimidazole drugs or to those with cirrhosis ALBENDAZOLE
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THIABENDAZOLE It is a benzimidazole compound. It is a chelating agent that forms stable complexes with a number of metals, including iron, it does not bind calcium MOA: Probably the same as that of other benzimidazoles. The drug has ovicidal effects against some parasites. It causes irreversible liver failure and fatal Stevens-Johnson syndrome The drug should not be used in pregnancy or in the presence of hepatic or renal disease
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MEBENDAZOLE It is a synthetic benzimidazole It has a wide spectrum of anti-helminthic activity It acts by inhibiting microtubule synthesis The parent drug appears to be the active form It is indicated for use in ascariasis, trichuriasis, hookworm and pinworm infections Corticosteroids should be co-administered for severe infections Mebendazole is teratogenic in animals and therefore contraindicated in pregnancy. Plasma levels may be decreased by concomitant use of carbamazepine or phenytoin and increased by cimetidine Mebendazole is unsuitable for pregnant women or children less than 2 years old
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DIETHYLCARBAMAZINE Citrate (DCC) Removes the microfilariae from the blood and effect on the adult worms in the lymphatics It is choice in the treatment of filariasis (Elephantiasis), loiasis, and tropical eosinophilia replaced by ivermectin for the treatment of onchocerciasis. A synthetic piperazine derivative plasma half-life is 2–3 hours in acidic urine but about 10 hours if the urine is alkaline, a Henderson- Hasselbalch trapping effect. Dosage reduced in patients with persistent urinary alkalosis or renal impairment. MOA: It immobilizes microfilariae and alters their surface structure, Also displacing them from tissues and Making them more susceptible to destruction by host defense system
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Uses: The drug should be taken after meals. Filariasis Wuchereria bancrofti, brugia malayi, Brugia timori, and Loa loa Microfilariae of all species are rapidly killed adult parasites are killed more slowly Antihistamines may be given for the first few days of therapy to limit allergic reactions Corticosteroids should be started and doses of diethylcarbamazine lowered or interrupted if severe reactions occur DIETHYLCARBAMAZINE Citrate (DCC)
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IVERMECTIN It is drug of choice in strongyloidiasis and onchocerciasis It is a semisynthetic macrocyclic lactone It is a mixture of Ivermectin B1a and B1b. derived from soil actinomycete Streptomyces avermitilis It is used only orally in humans. In onchocerciasis, it is microfilaricidal MOA: It appears to paralyze nematodes and arthropods by intensifying GABA–mediated transmission of signals increasing Cl−conductance in peripheral nerves. By binding to a novel allosteric site on the acetylcholine nicotinic receptor to cause an increase in transmission, leading to motor paralysis Onchocerciasis Strongyloidiasis (River blindness)
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ADRs: May cause corneal opacities and other eye lesions several days after treatment It is best to avoid concomitant use with GABA enhancing drugs Barbiturates, benzodiazepines, and valproic acid It should not be used during pregnancy Ivermectin - Macrocyclic lactone IVERMECTIN
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LEVAMISOLE It is effective in infections with the common roundworm (A. lumbricoides). It has a nicotine-like action, stimulating and subsequently blocking the neuromuscular junctions (NMJ). The paralyzed worms are then expelled in the faeces. But, ova are not killed.
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METRIFONATE (Trichlorfon) Used for the treatment of Schistosoma haematobium infections It an organophosphate compound Oral dose of 7.5–10 mg/kg is given three times at 14-day intervals MOA: It inhibits cholinesterase inhibition, This inhibition temporarily paralyzes the adult worms, resulting in their shift from the bladder venous plexus to small arterioles of the lungs, where they are trapped, encased by the immune system, and die ADRs: Transient cholinergic symptoms These symptoms may begin within 30 minutes and persist up to 12 hours. Metrifonate is contraindicated in pregnancy. S. haematobium
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NICLOSAMIDE It is a salicylamide derivative It is a second-line drug for the treatment of most tapeworm infections Taenia saginata (Beef tapeworm), T. solium (Pork tapeworm), and Diphyllobothrium latum (Fish tapeworm) Adult worms (but not ova) are rapidly killed, due to inhibition of oxidative phosphorylation or stimulation of ATPase activity The scolex (the head of the worm that attaches to the host intestine) and a proximal segment are irreversibly damaged by the drug, such that the worm separates from the intestinal wall and is expelled. For T. solium, the drug is given in a single dose after a light meal, usually followed by a purgative 2 h later in case the damaged tapeworm segments release ova, which are not affected by the drug.
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OXAMINEQUINE It is used for the treatment of Schistosoma mansoni infections Oxamniquine, a semisynthetic tetrahydroquinoline Contraction and paralysis of the worms results in detachment from terminal venules in the mesentery and transit to the liver, where many die; surviving females return to mesenteric vessels but cease to lay eggs. has been effective in instances of praziquantel resistance. Use: Advanced hepatosplenomegaly Drug makes many patients dizzy or drowsy, It should be used with caution in patients whose work or activity requires mental alertness Oxamniquine is contraindicated in pregnancy Schistosoma mansoni
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PIPRAZINE It is an alternative for the treatment of ascariasis (Round worm) and threadworm/pinwarm (E. vermicularis) Cure rates over 90% MOA: It causes paralysis of ascaris by blocking acetylcholine at the myoneural junction; unable to maintain their position in the host, live worms are expelled by normal peristalsis It reversibly inhibits neuromuscular transmission in the worm, probably by mimicking, at GABA-gated chloride channels in nematode muscle It is administered with a stimulant laxative such as senna to facilitate expulsion of the worms.
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PIPRAZINE ADRs: Piperazine compounds should not be given to women during pregnancy, to patients with impaired renal or hepatic function, or to those with a history of epilepsy or chronic neurologic disease Urticaria and bronchospasm Ascariasis E. vermicularis
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PRAZIQUANTEL It is a synthetic isoquinoline-pyrazine derivative It is used in the treatment of schistosome infections of all species (Schistosomiasis) The drug of choice for all forms of schistosomiasis Schistosoma haematobium; S mansoni or S japonicum. It is also effective in cysticercosis The drug's safety and effectiveness as a single oral dose have also made it useful in mass treatment of several infections Its plasma concentrations increase when the drug is taken with a high-carbohydrate meal or with cimetidine; Bioavailability is markedly reduced with some anti-epileptics (phenytoin, carbamazepine) or with corticosteroids
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PRAZIQUANTEL MOA: It appears to increase the permeability of trematode and cestode cell membranes to calcium, resulting in paralysis, dislodgement, and death Disrupts Ca2+ homeostasis in the Parasite Binding to consensus protein kinase C-binding sites in a β-subunit of schistosome voltage-gated calcium channels also disrupts the tegument of the parasite Unmasking novel antigens, and as a result it may become more susceptible to the host’s normal immune responses
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PYRANTEL PAMOAT It is a tetrahydropyrimidine derivative It is active mainly against luminal worms (pinworm/hookworm - Necator americanus) MOA: It is a neuromuscular blocking agent that causes release of acetylcholine and inhibition of cholinesterase; this results in paralysis, which is followed by expulsion of worms. It is effective against mature and immature forms of susceptible helminths within the intestinal tract but not against migratory stages in the tissues or against ova It should be used with caution in patients with liver dysfunction Hookworm
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Resistance to anthelminthic drugs It is a widespread and growing problem affecting Parasites that develop such resistance pass this ability on to their offspring, leading to treatment failure. The widespread use of anthelminthic agents in farming has been blamed for the spread of resistant species. Molecular mechanisms that contribute to drug resistance 1. The presence of the P-glycoprotein transporter 2. Alterations in their high-affinity binding to parasite β-tubulin. 3. Changes in the structure of the target acetylcholine nicotinic receptor
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Principal drugs used in helminth infections
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Summary of Anti-helminthics
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THANK YOU FOR YOUR ATTENTION