Anti helminthic drugs

Basics on Antihelmitics

1. Anti Helminthic Drugs Binaya Subedi BDS 4 th batch Chitwan Medical college

2. Introduction Helminthes; means worms Helminthiasis is prevalent globally; 1/3 rd of world population harbor them. But, more common in developing countries with poorer personal and environmental hygiene. They are commonly transmitted through feco -oral route thus GIT becomes the common site of lodgment.

3. Symptoms Clinical symptoms arise mainly due to the toxins production . Acute or chronic blood loss leading to anemia . Dysentery, Diarrhoea Abdominal pain Subcutaneous nodules Allergic Reactions, Urticaria Injury to the visceral organs Intestinal or lymphatic obstruction Conjunctivitis , Retinitis, Blindness Hepatosplenomegaly

4. Classification of Helminthes Class Example Tapeworms ( cestodes ) Taenia solium ,  Taenia saginata , Hymenolepis nana ,   Echinoccocus granulosus Flukes ( Trematodes ) Schistosoma , Fasciola hepatica Roundworms (Nematodes) Ascaris ,   Onchocerca ,  Trichuris , Neactor americanus , Anchylostoma duodenale

5. Pharmacological targets Helminths depend on host glucose for their basic metabolism . So, glucose uptake can be blocked. Eg : Benzoimidazoles , Levamisole They have moderately developed muscular system which can be stimulated or inhibited to produce tonic or flaccid paralysis through different receptors mediated mechanisms . Eg : Piperazine , pyrantel pamoate , Levamisole They produce energy by anerobic pathway as well as from oxidative phosphorylation . Eg : Niclosamide Cell membrane acts as barrier between internal and external environment which can be perforated, surface adhesion molecules can be altered. Eg : DEC, Praziquantel

6. Anti H elmintics Drugs Classification Benzimidazoles : albendazole , mebendazole , thaibendazole Pryantel pamoate Diethyl carbamazine : DEC Ivermectin Levamisole Salicylanilides : Niclosamide Praziquantel

7. Choice of Drugs for Helminths

8. Mebendazole Benzimidazole ; congener of thiabendazole Became popular because of it retained board spectrum antihelmintic activity but not the toxicity of it’s predecessors. 100% cure rate/ reduction in egg count in roundworm, hook worm, Enteroius , Trichuris infestations but much less active on Strongyloides . Upto 75% cure reported in tapeworms. H. nana is relatively insensitive. Action of mebendazole is rather slow, takes 2-3 days to develop. Poor intestinal absorption (10-15%).

9. Contd.. Mechanism of action: It binds to ß- tubulin of susceptible worms with high affinity and inhibits its polymerization It acts probably by blocking glucose uptake by parasites and depletion of its glycogen stores. Microtubules in the worms are gradually lost. ADRS: Well tolerated even by the pts. with poor health. Diarrhea , nausea and abdominal pain Expulsion of Ascaris from mouth and nose has occurred. (Starvation) Allergic reactions, loss of hairs, and granulocytopenia at high dose.

10. C/I: Pregnancy. (being based on animal data). Uses: T/t of multiple infestations (Roundworm, hookworm, whipworm, Enterobius , Trichinella Spiralis , Hydatid disease) Trichuriasis (effective than albendazole ) Mass treatment but need of large dose is a drawback.

11. Albendazole Congener of mebendazole with retained board spectrum anti helmintic activity and well tolerability. Adv: Single dose is enough in many cases. Eg : Ascariasis , Hookworm and Enterobiasis . (3 day treatment with mebendazole ) Superior to Mebendazole in S trongyloidosis , Hookworm, Hydatid disease. But, inferior in Trichuriasis . MOA: Similar to that of Mebendazole .

12. ADRS: GI side effects (abdominal pain, diarrhea, bowel upset, n/v Dizziness in few cases headache, fever, alopecia, jundice , neutropenia in prolonged use Note: It should be given in empty stomach for intestinal worms but for cysticercosis , hydatid disease and cutaneous larva margins it should be given with fatty meal. Uses: Ascaris , Hook worm, Enterobius , Trichuris infestations. (400mg, 200 mg) Tapeworm and strongyloidosis Neurocysticercosis (400 mg BD for 8-15 days) Cutaneous Larva margins Hydatid disease Filariasis

13. Thiabendazole First benzimidazole introduced, polyantihelmintic , practically covers all species of nematodes. Also inhibits development of egg and kills the worm. MOA: as same of mebendazole Also exerts antipyretic, analgesic and anti-inflammatory effect. Contributes in cutaneous larva margin and larva or worm induced inflammation. ADRS: N/V, loss of apatite, headache are common. Impaired alertness, interferes with normal activities Itching, abdominal pain, diarrhea

14. Uses: practically against all nematodes infesting the GIT But, because of frequent side effects and poor patient acceptability it isn’t used regularly these days. It is used only when other better tolerated drugs are in effective.

15. Pyrantel pamoate High and comparable efficacy to that of mebendazole against Ascaris , hookworm, Enterobius . But less active against S trongyloids and inactive against Trichuris MOA: It causes activation of nAch receptors in worms resulting in persistent depolarization thus spastic paralysis . But, have very low affinity to human nAch receptors. ADRS: Almost free of side effects. Occasional GI symptoms, headache, dizziness has been reported. Safe during pregnancy.

16. Uses: For Ascaris , Ancyclostoma , and Enterobius ; single dose recommended For Nector and Strongyloides ; 3 day course Note: Piperazine though used for same purpose antagonize the action of pyrantel pamoate .

17. Piperazine Highly active drug against Ascaris and Enterobius with 90-100% cure rates. But, second choice of drugs these days. MOA: Causes hyperpolarization by GABA agonistic action opening Cl - channels resulting in relaxation, decreased responsiveness of worm muscles to Ach  flaccid paralysis Don’t effect NM transmission in man. ADRS: Safe and well tolerated. N/V, abdominal discomfort, urticaria Dizziness and excitement at high doses. Toxic dose produces convulsions and death d/t respiratory failure.

18. C/I: in Renal failure and in epilepticus . But safe during pregnancy. Uses : Ascaris and Enterobius infestations Intestinal obstruction d/t Ascaris In pregnancy when other anti- helmintics are contraindicated.

19. Levamisole , Tetramisole Tetramisole (D) and levamisole (L) are optical isomers. Levamisole is more active and more preferred. They are active against large number of nematodes but their use is restricted to only ascariasis and ancyclostomiasis because of poor action against other worms. MOA: They stimulate ganglia in worms and cause tonic paralysis  explusion of live worms. May also interfere with carbohydrate metabolism ( inh . Fumarate reductase ) ADRS: Nausea, abdominal pain, fatigue, drowsiness or insomnia is low.

20. Uses: Ascariasis Second line in A. duodenale infestations It was used: as DMARDS ?? as adjuvents in malignancies aphthotus ulcers Recurrent herpes But recurrent use produces reactions , not used now as immunomodulators .

21. Diethy Carbamazine Citrate (DCE) First drug for filariasis Highly selective effects on microfilariae (mf) MOA: Alters the mf membrane so that they are readily phagocytosed by tissue fixed monocytes but not by circulating monocytes . Muscular activity of MF is also affected causing hyperpolarization d/t piperazine moiety. ADRS: Not serious. Nausea, loss of appetite, headache, weakness and dizziness are usual. Rash, pruritus , lymphadenopathy , hypotension may occur d/t mass mf destruction. (If it occurs DEC is temporarily withheld and antihistamine and/or corticosteroids are given)

22. Uses: Filariasis : produces rapid symptomatic relief, mf disappears form the blood and pts. Becomes noninfective to mosquito in 7 days. Tropical eosinophilia Loa Loa and O. volvulus infections

23. Ivermectin Extremely potent semisynthetic derivative of antinematodal principle obtained from S treptomyces avermitilis MOA: It acts through special type of glutamate gated Cl - channel found only in invertebrates. Potentiates GABAergic transmission in the worms. The ultimate effect is tonic paralysis in worms. (Has low affinity for mammalian GABA receptors) ADRS: Mild side effects; Nausea, abdominal pain, constipation, pruritus , lethargy and transient ECG changes More important are d/t degradation products of MF as in DCE .

24. USES: DOC for single dose T/t for onchocerciasis and strongyloidosis Comparable to DCE for bancroftian and brugian filaria Highly effective in cutaneous larva migrans and ascaris A single 10-15 mg oral dose of ivermectin with 400 mg albendazole given annually for 5-6 years has been used for filariasis .

25. Niclosamide Highly effective against cestodes infecting man MOA: It acts by inhibiting oxidative phosphorylation in mitochondria and interfering with anerobic generation of ATP in tapeworm. Injured by niclosamide , they are digested in intestine but the degradation products are more hazardous. Why?? ADRs: Tastless and nonirritant, minimal absorption from GIT so minimal systemic toxicity Minor GI symptoms are produced. Malaise, pruritus , light headacheness It is safe during pregnancy.

26. Praziquantel Novel antihelmintic , board range of activity against trematodes ( S chistosomes ), cestodes but not nematodes. MOA: Rapidly taken by the susceptible worms and causes leakage of intracellular calcium  contracture and paralysis Loss of intestinal mucosal gripexpelled . ADRS: Bitter taste, nausea, abdominal pain Headache, dizziness and sedation. Uses: Tapeworm infestations Neurocysticercosis Schistosomes DOC for all flukes except liver fluke.

27. Any questions? References: Essentials of Medical Pharmacology, K.D Tripathi Deo’s Basics of clinical Pharmacology, Dr. Satish Deo Journel on Pharmacological Targets on Helminths , Dr. Arnold Grew https://en.wikipedia.org/wiki/Helminths https://web.opendrive.com/api/v1/download/file.json/72032104_QPWwd_e5e1?inline=1 http://ebooks.cambridge.org/chapter.jsf?bid=CBO9780511546440&cid=CBO9780511546440A030

28. Thank You!!