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  1. 1. Dr Anant Khot Associate Professor Dept. of Pharmacology, AIIMS, Nagpur
  2. 2. Introduction  Problem statement: Infections with helminths affect > 2 billion people worldwide  Metazoa: Worms pathogenic for humans  Classification: 1) Round worms ( Nematodes) 2) Flat worms : a) Flukes ( Trematodes) b) Tapeworms ( Cestodes)
  3. 3. Nematodes  Major nematode parasites of humans include the, a) Soil-transmitted helminths ( STH’s) b) Filarial nematodes  Susceptible population- School aged children ( especially for STH infections)  Role of mass prophylaxis
  4. 4. Ascaris lumbricoides (roundworm) Trichuris trichiura (whipworm) Ancylostoma duodenale (Hookworms) Necator americanus Strongyloides stercoralis (threadworm) Enterobius vermicularis (pinworm) Trichinella spiralis (trichinosis) N E M A T O D E S
  5. 5. Cutaneous & visceral larva migrans Trichostrongylus species Angiostrongylus cantonensis W bancrofti, Brugia malayi, Loa loa Onchocerca volvulus (onchocerciasis) Dracunculus medinensis (guinea worm) Capillaria philippinensis (intestinal capillariasis)
  6. 6. Flukes (trematodes) Tapeworms (cestodes) Schistosoma haematobium (bilharziasis) Taenia saginata (beef tapeworm) Schistosoma mansoni & japonicum Diphyllobothrium latum (fish tapeworm) Clonorchis sinensis (liver fluke), Opisthorchis species Taenia solium (pork tapeworm) Paragonimus westermani (lung fluke) Cysticercosis (pork tapeworm larval stage) Fasciola hepatica (sheep liver fluke) Hymenolepis nana (dwarf tapeworm) Fasciolopsis buski (large intestinal fluke) Echinococcus granulosus (hydatid disease); Echinococcus multilocularis Metagonimus yokogawai (small
  7. 7. Drugs used in Rx helminthiasis  For nematodes: Benzimidazoles (BZ), Pyrantel pamoate, Ivermectin, Diethylcarbamazine (DEC)  For trematodes: Praziquantel  For cestodes: Albendazole, Niclosamide, Praziquantel
  8. 8. Benzimidazoles  M.O.A: Inhibition of microtubule polymerization by binding to β-tubulin  Biochemical changes:  Inhibition of mitochondrial fumarate reductase  Reduced glucose transport  Uncoupling of oxidative phosphorylation.
  9. 9.  Irreversible damage occurs in GI cells of the nematodes, resulting in starvation, death, & expulsion by the host  While highly injurious to nematodes, this fundamental disruption of cellular metabolism also offers treatment for a wide range of parasitic diseases.
  10. 10. Pharmacokinetics  Thiabendazole is soluble in water; mebendazole & albendazole are poorly soluble in aqueous solution  Mebendazole has low systemic bioavailability (22%) – poor absorption + rapid first-pass hepatic metabolism  Co-administration of cimetidine will ↑ plasma levels of mebendazole
  11. 11.  Albendazole- variable & erratic absorption  Absorption is enhanced by the presence of fatty food & by bile salts  Albendazole is rapidly metabolized to albendazole sulfoxide, which has potent anthelminthic activity  Albendazole sulfoxide ~ 70% PPB & has a variable plasma t1/2 of 4-15 hrs
  12. 12. Therapeutic uses  Thiabendazole- Cutaneous larva migrans (Thiabendazole (15%)- BD/TID for 5 days)  Mebendazole: It is an effective drug for treatment of GI nematode infections  For HAT infections: For Trichuriasis, it is better than Albendazole  Mebendazole 100 mg BD x 3 days
  13. 13.  A single 500 mg tablet administered once  If the patient is not cured 3 wks after Rx, a second course should be given  Enterobiasis: A single 100 mg is taken; a 2nd dose should be given after 3 wks  A/E: Mild GI Side effects  High doses: Allergic reactions, alopecia, reversible neutropenia, agranulocytosis & hypospermia
  14. 14.  Reversible elevation of serum transaminases- on long-term Rx  Mebendazole Rx → Occipital seizures  Mebendazole is teratogenic in animals & therefore contraindicated in pregnancy.  Note: WHO recommends its use for infected pregnant women in the 2 & 3 trimesters
  15. 15. Albendazole  In STH infestation →For adults & children >2 yrs age- Rx is single dose 400 mg orally  Hydatid Disease → is the T.O.C for medical therapy & is a useful adjunct to surgical removal or aspiration of cysts  Dose: 400 mg twice daily with meals for 28 days, THEN 14 drug-free days x 3
  16. 16.  Neurocysticercosis → for symptomatic parenchymal or intraventricular cysts Dosage: 400 mg BD for up to 21 days.  Microsporidial intestinal infections in patients with AIDS  It is combined with either DEC or ivermectin in programs directed toward controlling lymphatic filariasis
  17. 17. Adverse effects  Transient mild GI symptoms ~ 1% of treated individuals  M.c side effect is liver dysfunction  Other S/E- severe headache, fever, fatigue, loss of hair, leukopenia & thrombocytopenia  Caution: Autoinduction  The safety in pregnancy & in children < 2 years of age has not been established.
  18. 18. Pyrantel Pamoate  It is a broad-spectrum antihelminthic, highly effective for treating pinworm, ascaris, and Trichostrongylus orientalis infections.  NM blocking agent that causes the release of acetylcholine & inhibition of
  19. 19.  Dose is 11 mg (base)/kg (Max- 1gm/dose) given orally once with or without food  For pinworm, the dose is repeated in 2 wks  A/E: Mild & transient, including nausea, vomiting, diarrhoea, abdominal cramps,
  20. 20. Piperazine derivatives  Piperazine: It is highly effective against both A lumbricoides & Enterobius vermicularis  M.O.A: It causes hyperpolarization of the ascaris muscles by GABA agonistic action  Opening Cl– channels causes relaxation & depresses responsiveness to the contractile action of Ach Flaccid
  21. 21. Salient features  It is often given with the purgative  Dose: Roundworm infestation- 4 gm OD for 2 consecutive days  Ability to relax ascarids, making it useful Rx of intestinal obstruction due to roundworm  It can be used during pregnancy
  22. 22. Diethyl carbamazine  Diethylcarbamazine, a synthetic piperazine derivative, is marketed as a citrate salt.  M.O.A: It immobilizes microfilariae and alters their surface structure, displacing them from tissues & making them more susceptible to destruction by host defense mechanisms.
  23. 23.  PK: It is rapidly absorbed from the GIT; after a 0.5 mg/kg dose, peak plasma levels are reached within 1–2 hours.  The plasma t1/2 is 2–3 hrs in the presence of acidic urine but about 10 hours if the urine is alkaline, a Henderson-Hasselbalch trapping effect
  24. 24. Therapeutic uses  For control & Rx of lymphatic filariasis  For Rx of tropical pulmonary eosinophilia  D.O.C for treatment of loiasis  Annual single-dose combination chemotherapy (DEC+Albendazole )– control of LF in areas where onchocerciasis and loiasis are not
  25. 25. Adverse effects  Therapeutic doses (6mg/kg)- Direct toxic reactions to DEC are rarely severe  Major A/E result directly or indirectly from the host’s response to destruction of the parasite  Delayed reactions to dying adult worms may result in lymphangitis, abscess
  26. 26.  Heavy Loa loa infestation– retinal haemorrhages & encephalopathy can occur  In patients with onchocerciasis, the Mazzotti reaction typically occurs within a few hours after the first dose  DEC is safe during pregnancy
  27. 27.  Other filaricidal drugs include:  Macrofilaricidal: Albendazole, doxycycline  Microfilaricidal : Ivermectin
  28. 28. Ivermectin  It is a semisynthetic macrocyclic lactone derived from the soil actinomycete Streptomyces avermitilis.  M.O.A: It appears to paralyze nematodes & arthropods by intensifying GABA–mediated transmission of signals in peripheral nerves.
  29. 29.  PK: 3/6 mg tablet taken on an empty stomach  The drug has a wide tissue distribution; but does not enter CNS, sequestrated in liver & fat  It has a long terminal t1/2~ 57 hrs.  Excretion of the drug and its metabolites
  30. 30. Uses  Onchocerciasis  Strongyloidiasis  Lymphatic filariasis – in regions where onchocerciasis, loiasis or both are endemic  It is effective in controlling scabies, lice, & cutaneous larva migrans & in
  31. 31. Adverse effects  In filarial infection, it causes a Mazzotti- like reaction to dying microfilaria  In strongyloidiasis treatment, infrequent adverse effects include fatigue, dizziness, nausea, vomiting, abdominal pain, & rashes.  In onchocerciasis treatment, adverse effects are principally from the killing of microfilariae and can include
  32. 32.  Fever, headache, dizziness, somnolence, weakness, rash, increased pruritus, diarrhoea, joint and muscle pains, hypotension, tachycardia, lymphadenitis, lymphangitis, and peripheral oedema.  Some patients develop corneal opacities and other eye lesions
  33. 33. PRAZIQUANTEL  M.O.A: ↑ Cell permeability to calcium → uncontrolled calcium influx →↑ muscle contraction & paralysis  Tegument vacuolization & disintegration  PK: Given PO, absorption enhanced by food  Plasma t1/2 is short (1.5 hrs)
  34. 34. Uses  Tapeworm infestation:  T.saginata & T.solium-10 mg/kg single dose  H Nana, D Latam- 15-25 mg/kg single dose  Neurocysticercosis: 50 mg/kg TDS for 2 wk
  35. 35. Adverse effects  Headache, dizziness, drowsiness, & lassitude; others include nausea, vomiting, abdominal pain, loose stools, pruritus, urticaria, arthralgia, myalgia, & low-grade fever.  In neurocysticercosis, neurologic abnormalities may be exacerbated by inflammatory reactions around dying
  36. 36. Niclosamide  Adult worms are rapidly killed due to the inhibition of oxidative phosphorylation or stimulation of ATPase activity.  Injured tapeworms are partly digested in the intestine (T solium-dead segment release ova larva formation-penetrate its wall & cause visceral cysticercosis
  37. 37. Uses  The adult dose of niclosamide is 2 g once, given in the morning on an empty stomach.  Single treatment is effective for D. latum, T. saginata, and T. solium tapeworms.  H diminuta & D caninum infections are cured with a 7-day course of treatment
  38. 38. Others  Triclabendazole-Approved for treatment fascioliasis in persons ≥6 years of age.  Bithionol is an alternative to triclabendazole for the Rx of fascioliasis & an alternative to praziquantel for the Rx of paragonimiasis.  Doxycycline-filariasis and
  39. 39.  Metrifonate (trichlorfon): It is a safe, low- cost alternative drug for the treatment of Schistosoma haematobium infections  Moxidectin: Approved by the FDA in 2018 for the treatment of onchocerciasis in persons ≥12 years old.
  40. 40.  Oxamniquine: It is an alternative to praziquantel for the treatment of S mansoni infections
  41. 41. Thank you