Anti helminthes - 25-7-20

helminthes are common infections in developing and underdeveloped countries

1. Anti- helminthic drugs By Dr. ALKA BANSAL Associate Professor, Deptt . of Pharmacology, SMSMC, Jaipur

2. Introduction Helminths are macroscopic pathogenic organisms which cause disease of intestine and/ or tissues in human. Trematodes and cestodes together are called flatworms or platyhelminths.Nematodes are also called roundworms.

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4. 2 / 16 / 2015 Dr. Nehal Afifi 11 Table : Common Helminths infestation Cestodes(tapeworms) Intestinal adult worms Taenia saginata Taenia solium Diphyllobothrium latum Beef tapeworm Pork taperworm Fish tapeworm Larval tissue cysts Taenia solium Echinococcus granulosus Cysticercosis Hydatid disease Nematodes( round worm) Tissue worms Intestinal nematodes W uchereria bancrofti , B malayi , O volvulus Dracunculus medinensis Trichnella spiralis Enterobius vermicularis Ascaris lumbricoides Trichuris trichiura Ancylostoma duodenale , N. americana St r ong y loid e s s t e r c or a lis Filariasis Guinea worm P in worms Round worms Whipworm Hookworm Threadworm Trematodes (flukes) Blood flukes Intestinal / hepatic flukes Lung flukes Schistosoma species Fasciola hepatica Fasciola gigantica Paragonimus westermanii Schistosomiasis

5. Types of Common Helminthes Taenia solium( Pork ), 1. Gastrointestinal worms A- Tape worms ( cestodes ) Taenia saginata ( beef ) Diphylobothrium latum ( fish ) 3 Worms live in hosts GIT. Worms or larvae live in other tissues of hosts ꞌ body like muscles , viscera , meninges , lungs, subcutaneous tissues. In case of D. latum infections by eating raw or undercooked fish

6. B- lar . Tapeworm T issue t apeworms In some conditions larvae may develop causing cysticercosis by T. solium (i.e. larvae gets encysted in muscle , or more seriously in brain or eye ) . cysticercosis 4 i

7. - Hydatid tape worm - Echinococcus granulosus . These are cestodes ,primary in canines (dogs) and sheep as intermediate host. Humans can act as i ntermediate host in which larvae develop to hydatid cyst within the tissue . Hydateid cyct 7

8. Life cycle of Echinococcus granulosus 8

9. 2- INTESTINAL ROUND WORMS ( NEMATODES ) Ascaris l u mubrico i ds ( common round worm ) Enterobius vermicularis ( pin worm ) Trichuris trichuria ( whip worm ) Strongyloids stercoralis ( thread worm ) Ankylostoma du o denale ( hook worm ) B. TISSUE ROUND WORMS 8 Trichinela spiralis

10. 9 Ascaris lumbricoids (Comm R.W.) Hook worm Ancylostoma duodenale Tricuris tric h ura Whip w orm Pinworm male ,female

11. 3- Trematode ( schisotomes , FLUKES) Schistosoma → SCHISTASOMIASIS , BILHARZIA Flukes( Leaf Like ) Lung fluke: larvae move from intestine & settle in lungs 10 Fasiola hepatica Dircrocoelium dendriticum

12. Anthelmintic Drugs i 12 Anti : against & helminthes : worms Dru g s kil l or ex p el the in t ernal para s i t ic w orms in f esting GIT & other tissues of man and animals . Helminths harm by depriving of food, causing blood loss, injury to organs, intestinal or lymphatic obstruction and by secreting toxins.

13. Ideal Anthelmintic drug Dr. Nehal Afifi 2/16/2015 13 - A wide therapeutic index; at least 1: 6 with highest toxicity to worms, but lesser toxic to the host - Broad spectrum of activity against mature & immature larval worms. - Easily administered and have a pleasant taste. - Effective Orally , less number of doses . - Economic (inexpensive) and compatible with other drugs. -I nhibit reinfection for extended periods.

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15. Classification of Anthelmintics 2/16/2015 Dr. Nehal Afifi 15 According to the type of action : Vermicide : Drugs that kill worms ( Praziquan tel ) Vermifuge : Expel infesting worms alive ( Piperazine ) According to the spectrum of activity: Narrow spectrum Anthelmintics Broad spectrum Anthelmintics According to source: Natural and Synthetic

16. Contd … A-Broad spectrum- 1. Effective against all three categories of helminths – benzimidazoles – mebendazole , albendazole 2. Against trematodes and cestodes-praziquantel 3. Against many nematodes- pyrantel pamoate B-Narrow spectrum - They are further sub-divided into 1. For certain nematodes only-, levamisole , piperazine , DEC, ivermectin , triclabendazole , thiabendazole 2. For cestodes only - niclosamide 3.For trematodes only- metrifonate , oxamniquine , bithionol

17. CLASSIFICATION ON THE BASIS OF MECHANISM OF ACTION i . Inhibit polymerization of beta tubulins (and energy production): Benzimidazoles like mebendazole , albendazole ii- NN receptor agonist (cause spastic paralysis): Pyrantel pamoate , Levimasole iii- GABA- A agonist (cause flaccid paralysis ): Piperazine iv-Glutamate gated Cl - channel (tonic paralysis): Ivermectin v Increase phagocytosis by altering microfilarial membrane: DEC vi- Increase calcium influx( tonic paralysis): Praziquantal vii- Uncoupling of oxidative phosphorylation : Bithionol , Niclosamide

18. Antin e m a tod a l dru g s 25 Drugs kill or expel round worms (nematodes) infesting man & animals Classification of Antinematodals: I- Organic of plant origin: 1- Nicotine sulphate: i nhibit cholinergic nerves of worms leading to muscular paralysis and expelling of worms. 2- Santonine 3- Chenopodium oil: pale yellow volatile oil from American wormseed plant. Oil contain a mixture of volatile subs. & active principle ( Ascaridol ). Ascaridol acts as a vermifuge by causing muscular paralysis of worms and expel them outside Oil given orally in soft gelatinous capsules.

19. II- Synthetic drugs : 1- Benzimidazoles ( Albendaz o le , Thiabendaz o le , Triclabendazole , Mebendazole , Oxfendazole , Fenbendazole & Flubendazole ). Albendazole - broad spectrum vermicide , active against adult liver flukes, cestodes &GIT nematodes larvae . On contrast, Tricalbendazole is highly active against liver flukes (fasciolicide), but has no activity against nematodes & cestodes 27

20. MOA: Benzimidazoles a re synthetic vermicide which primarily acts by binding to β tubulin and inhibiting the microtubule polymerization. Other supported mechanisms of action are inhibition of mitochondrial fumerate reductase , and inhibiting energy production, uncoupling of oxidative phosphorylation,reduced glucose transport and glycogen synthesis - are very safe anthelmintics ; a wide safety margin from1 : 20 for albendazole to 1: 100 for fenbendazole (very safe).

21. Albendazole Drugs of choice in Ascaris , necator , enterobius , ancyclostoma in single dose of 400mg. It is taken for three days for heavy infestation. Dose is reduced to 200mg in children less than two years. In enterobius second dose is given two weeks apart. For Tapeworms , Strongyloides ,- 400mg OD for three days. For Trichinella 400mg BD for three days but not effective on larva migrated to muscles. For Cutaneus larva migrans caused by Ancylostoma braziliense and Ancylostoma caninum - 400mg OD for 3-5 days . 5. In Visceral larva migrans by Toxocara canis and catti-400mg BD for 28 days

22. 6. Neurocysticercosis caused by T. solium cercarie reaching the brain -400mg BD for 3 to 28 days. (Steroids and anticonvulsants are added to suppress the inflammation and to check the convulsions. Albendazole is preferred over praziquantel for its better penetration, high cure rate, shorter duration of action and is cheaper). 7.Hydatid disease by Echinococcus granulosis , alveolar echinococcosis by E. multilocularis-400mg BD for28 days. 8. Alternative and equally effective drug for- trichuriasis , enterobius in 400mg single dose. 9. Clonorchicsinensis (liver fluke) - 400mg BD for 7 days.

23. Prophylaxis- 9. Filariasis – 400 mg albendazole yearly added to DEC/ Ivermectin as adjuvant for mass prophylaxis as recommended by WHO. 10 . Other uses of albendazole are T vaginalis , G lamblia , microsporidial species ( enterocytozoonbieneusi , encephalitozoon intestinalis ) which cause intestinal infection in AIDS.

24. Mebendazole Drug of choice in Trichuriasis and multiple infestations by roundworm-100 mg BD for three consecutive days. Alternative to Albendazole in- 2. Pin worm- 100 mg single dose for 2years and above,repeated after 2-3 weeks if required. Maintain proper hygiene and treat all contacts simultaneously. 3. Ascaris / hookworm-100 mg BD for three days or 500 mg single dose (less effective) 4. Trichinella spiralis -200mg BD for four days. 5. Hydatid - 200-400 mg BD or TDS for three to four weeks. Alternative to metronidazole in guinea worm infection

25. Triclabendazole - liver fluke Thiabendazole - additional anti-inflammatory, analgesic, antipyretic properties. It can be applied locally for cutaneous larva migrans and trichinella two to three times daily for 5 days

26. PK &A/e - benzimidazoles - Well absorbed and tolerated even by patients with poor health. Albenda produces active sulfoxide moiety so potent &prolonged action Taken with fatty food especially for neurocysticercosis and hydatid disease. - include nausea, vomiting, abdominal pain diarrhea. -incidences of starvation of ascaris and its migration leading expulsion from mouth and nose have been reported eith mebendazole . Contraindication : Pregnancy

27. 2- Tetrahydropyrimidine derivatives ( Pyrantel , Oxantel , Morantel ) 30 Pyrantel pamoate: A broad specturm anthelmintic , highly effective against adult & larval nematode s . Not active against lung worms and whipworms. Oxantel : Narrow spectrum MOA: Pyrantel is a depol ari zing neuromuscular blocking agent ; cause release of acetylcholine & inhibition of cholinesterase enz. leading to muscular paralysis & death ( Vermicide ). Morantel in ruminants us e d as a drench or "protect bo l us" to provide prol o ng e d protection for 90 days ( slowly released).

28. 32 Pyrantel Clinical uses : For Pin worm, Ascariasis & ancyclostoma as a single dose of 10mg/kg and repeated after 2 wks . Three days course for Necator & strongyloides - Pyrantel given orally with or without food. No fasting , purging required. -

29. A/E -mild nausea, vomiting, diarrhoea , abdominal pain. -Contraindicated in pregnancy and in children less than 2 years. DI- Not given with piperazine as both have opposite mechanism of action. While pyrantel causes spastic paralysis, piperazine causes flaccid paralysis.

30. 3. Levamisole Levamisole : Effective against mature & immature larval GI round and lung worm ( ancyclostoma ) both orally & parenterally (2 nd line) . Very rapid action & expel worms within 24 hrs. Rapid absorbed from GIT- Metabolized by liver- Half life 3-4hr Levamisole acts also as an immunostimulant drug . MO A : N N ag o nist stimulate nic o ti n ic ga n glia in muscular paralysis & death of the worms(vermicide). Interfere with carbohydrate metabolism . Uses- age dependent dose in ascaris , RA, adjunct in malignancy, aphthous ulcer, recurrent herpes.

31. 4- Piperazine 34 Piperazine Commonly used antinematodal drug against only Ascaris and Oxyuris (pin) worms in man and animals. Not recommended for other helminthes infestation. Administered as citrate or phosphate salts and given orally . Moderate oral absorption & excreted unchanged in urine. MOA : act as vermifuge by its GABA agonist effect so it prevents neural transmission in the worm causing muscular paralysis and expelling of the worms alive. A very safe drug during pregnancy

32. 5 - Die t h y l Carbama z ine (DEC) 36 A highly soluble piperazine derivative → rapidly absorbed & distributed throughout the body. Drug of choice for treatment of Filariasis . Highly selective effect on microfilaria . Adult of O.volvulus is not killed. Enhances cell mediated immunity Safe for use in pregnant & young. MOA: DEC disrupt the microtubules & inhibit microtubules polymerization in microfilaria.

33. MOA: 1- DEC Immobilize microfilaria & alter their membrane structure displacing them from tissues & making them susceptible to destruction by host defense mechanism. 2.Alternation of microfilaria membrane → phagocytosed by fixed tissue monocytes. 3.Affect muscular activity and cause hyper polarization due to piperazine moiety. The drug should be given after meals . Uses: filariasis 2mg/kg TDS for 12 days to 21 days. tropical pulmonary eosinophilia A/e - febrile reaction; minimizedby low dose, antihistaminics , steroids

34. 6- Ivermectin ( endectocide ) 38 Endectocides are dr ugs effective against both arthropodes & nematode both. One of Avermectins that is h ighly effective against nematodes , mites , lice & ticks . has no activity against cestodes and flukes. Given orally or S/C at very low doses (o.2mg / kg ) MOA: act as vermicide causing paralysis of worms by i )special glutamate gated Cl - channels(absent in flukes, tapeworms) ii) intensifying the action of the inhibitory transmitter GABA at neuromuscular junction → paralysis and death of the worms.

35. IVERMECTIN Pharmacokinetics Rapidly absorbed & widely distributed . Does not cross BBB Half- life 2-3 days & Excretion mainly in feces . Uses: DOC for onchocerciasis (river blindness) and strongyloidosis (single dose) . Scabies, pediculosis given orally. With 400 mg albendazole annually for filariasis prophylaxis. A/e- mild pruritus , giddiness, nausea , abdominal pain, due to degradation products of Mf. Contraindication: Pregnancy . Concurrent use with other drugs that enhance GABA e.g Barbiturates, valproaic acid & b en zodiazepines .

36. Anti c es t od a l drugs Drugs kill or expel tape worms (Cestodes) infesting man & animals. Classification of Anticestodals: I- Organic of plant origin: 1. Arecoline: orally as vermifuge ,E ffective against Taenia species infesting dogs and cats. MOA : by inducing muscular paralysis of worms so lose their attachment with intestinal mucosa & increase intestinal motility of host ( as a neuromuscular purgative) → expel detached worms alive 2. Kamala powder : A red powder act as vermifuge due to its irritant effect so expels worms alive. Given orally and effective against cestodes infesting poultry

37. Niclosamide 19 A salicylanilide derivative Vermicide drug for treatment of tape worm infestation . N ot effective against cysticercosis or hydatic disease. MOA: Adult worm killed by inhibiting the mitochondrial phosphorylation process thus inhibiting energy production in worms. Pharmacokinetic: Niclosamide poorly absorbed & very rapidly excreted has a 5 to 7 folds safety margin Given in a single dose on empty stomach & a purgative use after 2 hrs because partial digestion may release eggs in t. solium which can then cause visceral cysticercosis .

38. Prazequ a ntel 22 A broad Spectrum ( Novel Anthelmintic) Actives against Cestodes – Schistosomes -Trematodes Effective against all adult , juvenile Cestodes & their larval forms in dogs & cats A potent schistosomicide with a high activity against Bl. flukes causing bilharziasis in man. MO A : Act as vermicide by 1- interfering with ionic balance due to leakage of IC Ca. from membrane causing rapid muscular contraction 2. causing vacuolation → disruption of worm tegument & death. . kinetics : Praziquantel given orally or (S/C) . Rapidly absorbed & metabolized safety margin reaches 1:40 of the recommended dose.

39. Uses : 10mg/kg single dose in tapeworm All schistosomes and flukes except F. hepatica ( triclabendazole ) DI- phenytoin , carbamazepine , dexamethasone induce its metabolism and decrease bioavailability. A/e- nausea, abdominal pain, headache, sedation, itching, urticaria , neurological complications due to destruction of cysticerci in brain. Old fasciolicides : 1-Carbon tetrachloride ( CCl 4): by inhibiting the metabolic enzyms present in mature flukes. 2- hexachloroethane

40. Important i 41 Miscellaneous limited spectrum drugs- 1- Nitazoxanide - comparable to albendazole for treatment of  Ascaris  infections and is approved for use in children ≥12 months of age. 2-Artemisin based therapy – artether shows promise as anti- schistosomal 6mg/kg once every 2-3 weeks. 3-Against flukes – i-Bithionol - it is useful against liver and lung flukes ii- Metrifonate – it is an alternative drug effective against Schistosoma hematobium ( blood fluke causing bilharziasis ). iii- Oxamniquine - Schistosoma mansoni  

41. Summary- 1. Soil - transmitted helminths    : Ascaris lumbricoides , whipworm ( Trichuris trichiura ), and hookworm ( Anclostoma duodenale and Necator americanus ). 2.Schistosomes,  Ancylostoma , and  Necator  get into your feet from the  SAN d.You could get sick if you  EATTT   Enterobius ,  Ascaris ,  Toxocara ,  Trichinella , Taenia . 3. black  in  onchocerciasis : spreads through  black  flies, causes  black  skin nodules and blindness known as r IVER  blindness and treated with  IVER mectin .

42. 4-For nematodes albendazole / mebendazole are used except filarial (DEC, ivermectin ) , threadworm ( ivermectin )and guinea worm( metronidazole ) 5-For trematodes praziquantal is used except fasciola hepatica In F hepatica triclabendazole is doc, alternative is bithionol . Praziquantel is not effective 6- Alternative for each schistosomal infection are S.japonicum - niridazole;S . hematobium-metrifonate;S . mansoni-oxamniquine . 7-The primary drugs used for cestode   infections  are albendazole (in neurocysticercosis and dog tapeworm) and praziquantel . 8- Drugs safe in pregnancy- piperazine , praziquantel , niclosamide , DEC.

43. Q&A Questions and Answers Q1- A child of five years presented with complaints of abdominal pain and peri - anal pruritus . Microscopic examination of an adhesive tape sticked to perianal area revealed small, white, round worms and transluscent eggs. Which is the best treatment for this child? (A) Fluconazole (B) Mebendazole (C) Metronidazole (D) Praziquantel

44. Q2-An adult gave history of eating pork and he was found to be infested with both tapeworm and schistosomes . Drug which is effective against both is- (A) Praziquantel (B) Albendazole (C) Niclosamide (D) Ivermectin

45. Q3. Drug of choice for cutaneous larva migrans , visceral larva migrans and neurocysticercosis is Mebendazole Albendazole Praziquantel Triclabendazole Q4.Drug approved for topical treatment of inflammatory rosacea DEC Albendazole Mebendazole Ivermectin

46. Q5. Drug of choice for river blindness is Ivermectin DEC Piperazine Metronidazole Dr. Nehal Afifi 42 2/16/2015 n m

47. Thank you Thank you