Anthelmintics

1. Anthelmintics Dr\ Moustafa K Soltan

2. Anthelmintics. (Anti = against, helminthes = worms) Vermicides: Drugs that kill worms Vermifuges :Drugs that expel the worms from the body by 1)Peristaltic movement of intestine, or 2)cathartic and purgative action. Characters of ideal anthelmintics: 1) Orally active. 2) Effective in single dose. 3) Inexpensive. 4) Wide safety margin between toxicity to worm and toxicity to host

3. ** Classification of Helminthes: they are two phyla Phylum: Nemathelminthes. Class: Nematodes (true round worms) I) Intestinal Nematodes: 1) Round worms as Ascaris. 2) Hookworms as Ancylostoma. 3) Pinworms as Oxyuris. 4) Whipworms as Trichuris. 5) Thread worms as Strongyloids. 6) EnterobiusVermicularis. II) Tissue Nematodes:Filaria. Phylum: Platyhelminthes ( flatworms) Class: Termatodes ( Flukes ) 1) Liver flukes: Fasciola Hepatica. Fasciola Gigantica .2) Blood flukes: Schistosoma haematobium. Schistosoma mansoni. 3) Intestinal flukes: Heterophyes heterophyes. Class: Cestodes ( Tapeworms ) Beef tapeworm:Taenia saginata. Pork tapeworm:Taenia solium. Dwarf tapeworm:Hymenolepis nana.

4. A] Drugs active on Nematodes: I] Chlorinated compounds: CCl4 , tetrachloroethylene. II] Piperazine derivatives: piperazine citrate, diethylcarbamazine citrate. III] Benzimidazole derivatives: Thiabendazole, Mebendazole, Flubendazole, and Albendazole. IV] Vinylpyrimidine derivatives: Pyrantel pamoate. V] Dyes:( cyanine dyes ): Pyrivinium pamoate VI] Imidazothiazoles: Levimasole.

5. I] Chlorinated compounds: CCl4 , tetrachloroethylene. CCl4 Must be followed by purgative to remove dead worms and excess drug. **Its side effects are 1)liver necrosis. 2) not used during pregnancy, otherwise make liver and kidney damage to the fetus tetrachloroethylene. MOA: Cause irritation to the worm tissue. Used in Treatment of roundworm infestations. Less toxic than CCl4, but all halogenated hydrocarbons cause liver and kidney degeneration II] Piperazine derivatives: piperazine citrate, diethylcarbamazine citrate

6. Synthesis of piperazine citrate:

7. Piperazine citrate.Block the response of Ascaris muscle to acetylcholine at neuromuscular junction causing flaccid paralysis in worms which become easily dislodged by gut movement, expelled in faeces .Treatment of roundworms as ( Ascaris ),Or pinworms like ( Enterobius vermicularis or Oxyuris) infestations. DiethylCarbamazineCitrate.1) same to that of piperazine citrate due to piperazine moiety.2) diethylcarbamazine cause alterations in the microfilarial surface membranes, thereby rendering them recognized as foreign bodies by the host and destroyed by its defense mechanism 1) drug of choice in treatment of filariasis.2) active against ascariasis. ( note that piperazine citrate and diethyl carbamazine citrate are vermifuges and note the mechanism, while diethylcarbamazine citrate is vermicide for filarial ).

8. III] Benzimidazole derivatives:

9. Synthesis of thiabendazole SAR of benzimidazole derivatives 1) 5-substituents do not necessary increase potency, `But when R in C5 is group prevent metabolic inactivation such as hydroxyl group, the resulting compound has greater anthelmintic activity. 2) 2-substituents may be methyl carbamate (--NHCOCH3 ) or an aromatic ring without loss of anthelmintic potency, but those with aromatic or heterocyclic ring are more toxic than those with carbamate. ( thiabendazole is the most toxic one).

10. Mode of action: • inhibition of certain enzyme: which is fumarate reductase system of the worm thereby interfering with an important energy source. • 2)-inhibition of the cell division: inhibit nematode cell division in the metaphase by interfering with the microtubule assembly • 3)-They have high affinity for tubulin, the precursor protein, necessary for microtubule synthesis. • 4)-they make irreversible blockade of glucose uptake by susceptible helminthes, so depletion of glycogen stored within the parasite leads to decrease in ATP, which is responsible for survival and reproduction in helminthes.

11. No need for purgative use after oral administration **all of them have broad spectrum anthelmintic activity mainly against intestinal nematodes, but, 1) thiabendazole also used in treatment of cutaneous larva migrans. 2)mebendazole , flubendazole and albendazole effective in some cestode worms. ** side effects of mebendazole and albendazole: GIT side effects in normal doses. Liver impairment, bone marrow depression in high doses. Should not given in pregnancy as teratogenic can cross the placenta

12. 3) Thiabendazole in which benzimidazole ring is replaced by other rings like imidazopyridine are usually less active than the parent drug. 4) mebendazole, flubendazole, albendazole are less toxic than thiabendazole due to: a- they don not have heterocyclic ring in 2 position. b- they are less absorbed from the GIT after oral administration than in case of thiabendazole that is readily absorbed from the GIT. Vinylpyrimidine derivatives: Pyrantel pamoate.

13. Synthesis Pyrantel Pamoate. Depolarizing neuromuscular blocking agent that produce spastic paralysis in susceptible helminthes followed by their expulsion from host. ( as pyrivinium pamoate and piperazine derivatives ).* * used in most intestinal nematode infection like pinworms and roundworms (except whipworms).** piperazine may antagonize the effect of pyrantel so they must not be used together.

14. Dyes:( cyanine dyes ). 6-(dimethylamino)-2-[2-(2,5-dimethyl-1-phenylpyrrol-3-yl)vinyl]-1-methyl quinolinium salt with 4,4- -methylene bis [3-hydroxy-2-naphthoate]. PyriviniumPamoate.Exert anticholinergic effect on the worms causing paralysis and expulsion by peristalsis ( vermifuges by the same mechanism of piperazine derivatives that is depolarizing neuromuscular blockers)** used for chemotherapy of pinworms.**Side effects: nausea, epigastric pain due to local irritant effect.** drug is red cyanine dye, so leads to reddish brown stool

15. Imidazothiazoles. Levamisole.1) act as Depolarizing neuromuscular blocking agent and as above in pyrantel pamoate.2) potent stereospecific inhibitor of fumarate reductase in various nematodes, such inhibition causes contraction in helminthes, followed by tonic paralysis, subsequent elimination of the worm. ** used for treatment of round worm as Ascariasis, and hook worm as ancylostomiasis.** completely absorbed from the GIT, the levo isomer is the only active one.

16. Drug active on cestodes Synthesis of niclosamide.

17. Niclosamide.1) interfere with helminthes metabolism where it inhibits mitochondrial oxidative phosphorylation, inhibit respiration, block glucose uptake by the cestode.2)after initial attack of the drug,helminthes ( taenia solium ) become highly sensitive to the proteolytic enzymes of the host intestine, undergo partial digestion. ** the drug of choice in treatment of most tapeworm infestations. (cestodes) such as Taenia saginata, Taenia solium, Hymenolepis nana. ** the drug of choice in treatment of most tapeworm infestations. (cestodes)** no systemic absorption of the drug occurs .** the digestive juice of the host facilitates the drug penetration into various cestodes. ** very important note:in case of Taenia solium, ( pork tapeworm):laxative should be given within 1-2 hours after drug use to expel the dead worms and to avoid cysticercosis [ as the drug is not active against the larval form (cystcerci)].This cysticerci results from release of live ova from worm segments damaged by the drug and migrate to the stomach.( now praziquantil is the drug of choice in case of Taenia solium to avoid such limitation)