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Pharmcotherapy of helmintic infections
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- 3. What is thediagnosis and pharmacological management? The same patient developed fever, urticaria, swollen and tender lymph nodes tachycardia, hypotension, and abdominal pain within seven days of treatment .. A.What is this known as ? B. Why this has happened and how would you manage this patient
- 4. At the endof the lecture, the students will be able to.. 1. List out the drugs for pharmacotherapy of Nematodes, Trematodes and Cestodes. 2. Explain the mechanism of action of the drugs 3. Enumerate the pharmacological actions, uses and adverse effects of the drugs
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- 8. Helminthis infections Deprivation of food Bloodloss Lymphatic obstruction Injury to organs
- 9. Drug treatment Health education Improvedsanitation
- 10. Drugs –Vermicide Vermifuge Infestinghelminths. Aim at metabolic targets present in parasite Should be absent from or have different characteristics than those of the host GOAL Elimination from host Control spread of infection Reduce transmission
- 11. Wide safety ofmargin with highest toxicity to worms Wide therapeutic index Broad spectrum activity Activity against mature and immature stages Lack of side effects/toxicity Ease of administration (preferably single dose) Low cost.
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- 16. Benz-imidazole - congenerof thiabendazole Broad-spectrum anthelmintic activity . Roundworm Hookworm (both species) Enterobius Trichuris Nearly 100% cure rate/reduction in egg count Strongyloides. Less sensitive Trichinella spiralis ExpelsTrichinella spiralis from intestines, but efficacy in killing larvae that have migrated to muscles is uncertain..
- 17. MOA SITE - Microtubularprotein ‘β-tubulin’ It binds to β-tubulin of susceptible worms with high affinity and inhibits its polymerization. Blocks glucose uptake in the parasite Depletes its glycogen stores Inhibits hatching of nematode eggs and their larvae Affected parasites are expelled in feces.
- 19. USES Roundworm Hookworm 100 mg twicea day for 3 consecutive days Whipworm 7 days Pin worm 100 mg single dose, repeated after 2–3 weeks (to kill the ova that have developed later). Trichinosis 200 mg BD for 4 days The dose and duration of treatment is the same for children above 2 years as for adults; ½ dose for 1–2 yr age.
- 21. Adverse effects Well toleratedeven by patients in poor health. Diarrhoea, nausea and abdominal pain Incidents of expulsion of Ascaris from mouth or nose have occurred, Allergic reactions, loss of hair and granulocytopenia Increased liver enzymes Prolonged treatment
- 22. Congener of Mebendazole: Broad spectrum Excellent tolerability Singledose administration Roundworm Hookworm (both species) Enterobius Trichuris Nearly 100% cure rate/reduction in egg count
- 23. Trichuriasis - inferiorto mebendazole. Strongyloidosis- more effective than Mebendazole Weak microfilaricidal action Cutaneous larva migrans. MOA - is similar to that of Mebendazole
- 24. PK Absorption- Well absorbedbut inconsistent, Enhanced when taken with fatty meal First pass metabolism Sulfoxide metabolite which has potent anthelmintic action. Albendazole sulfoxide is widely distributed in the body, enters brain,CSF Excreted in urine t½ of 8.5 hours.
- 25. USES No preparation orpostdrug fasting/ purging is required. For intestinal worms it should be given on empty stomach CI– Pregnant women Caution – Renal and hepatic disease Ascaris, hookworm, Enterobius and Trichuris: •A single dose of 400 mg •Three day treatment may be needed in heavy trichuriasis. strongyloidosis: •400 mg daily for 3 consecutive days. Trichinosis •Three day treatment expels the adult worm from intestine, but has limited effect on larvae that have migrated to muscles. They are not killed but symptomatic relief occurs. Corticosteroids are added if systemic manifestations are severe • Filariasis due to Wuchereria bancrofti, •Adjuvant •Added to diethylcarbamazine (DEC) or ivermectin, treating lymphatic filariasis
- 26. Side effects Well tolerated; Gastrointestinalside effects Dizziness,Insomnia Prolonged use, as in hydatid or in cysticercosis, has caused headache, fever, alopecia, jaundice and neutropenia.
- 27. Precaution No prior preparation,no fasting after the drug and no laxatives required Administered on an empty stomach for intra luminal worms but with fatty meals for tissue parasites CI Pregnancy, Children< 2yrs Drug Interaction Glucocorticoids and Praziquantel ↑albendazole sulfoxide
- 28. Benzimidazole Chelating agent andform stable complexes with metals including iron, but does not bind with calcium. PK Rapidly absorbed Half- life of 1-2 hrs Completely metabolized in liver 90% is excreted in urine (Glucuronide) Can also absorbed through skin Mechanism Of Action Similar to other benzimidazoles. It is ovicidal for some parasites
- 29. USES A/E •Should begiven after meals and tablets should be chewed •Strongyloidal infections & cutaneous larva migrans •Skeletal muscle symptoms produced by migration of Trichinella spiralis larvae to muscle •Thiabendazole cream is applied topically or drug can be given orally for 2 days. •More toxic than other benzamidazoles •GI disturbances •Pruritus, headache, drowsiness, psychoneurotic symptoms. •Irreversible liver failure. •Fatal •Stevens –Johnson syndrome •Not used in young children , pregnancy,
- 30. Efficacy against Ascaris,Enterobius and Ancylostoma is high and comparable to that of mebendazole. Lower cure rates (about 60%) - Necator infestation. Less active against Strongyloides Inactive against Trichuris and other worms. PK •Only 10–15% of an oral dose is absorbed • Partly metabolized •Excreted in urine
- 31. MOA Depolarizing, neuromuscular- blockingagent, Activation of nicotinic cholinergic receptors >Anticholinest erase Persistent depolarization Slowly developing contracture Spastic paralysis Expelled
- 32. USES A/E • Ascaris,,Ancylostoma andEnterobius:- a single dose of 10 mg/kg •. Necator and for Strongyloides - 3 days •No fasting, purging or other preparation of the patient is needed. •Infrequent mild transient GI disturbance •Drowsiness, headache, insomnia, rash, fever •Should be used with caution in liver dysfunction. CI- Pregnancy Children under 2 years
- 33. Ascaris and Enterobius; achieves 90– 100%cure rates. •Well absorbed •Partly metabolized in liver and excreted in urine. •Nausea, vomiting, abdominal discomfort and urticaria •Dizziness and excitement occur at high doses •Toxic doses produce convulsions •Death is due to respiratory failure It is contraindicated in renal insufficiency and in epileptics, Roundworm 4 g once a day for 2 consecutive days Pinworms 50 mg/kg (max. 2 g) once a day for 7 days
- 34. MOA GABA agonistic action Hyperpolarisationdue to opening of Cl¯ channels Relaxation and depresses responsiveness to contractile action of ACh Flaccid paralysis Worms expelled alive Purgative (senna) is given with it
- 35. Benzimadazole that.. 1) Hasa potent metabolite ?? 2) Has more incidence of SJS ?? 3) Is the DOC of whipworm
- 36. Active against manynematodes, Ascariasis and ancylostomiasis as a second line drug. 1) Stimulation of ganglia tonic paralysisExpulsion of worms 2) Inhibition of fumarate reductase interference in carbohydrate metabolism Ascariasis Single dose 150 for adults, 100 mg for children 20–39 kg body weight, 50 mg for 10–19 kg. Ancylostomias is Two doses at 12 hour intervals Immunomodulator restores depressed T cell function DMARD in RA malignancies, aphthous ulcers and Recurrent herpes •Well tolerated •Nausea,abdominal pain, giddiness, fatigue, drowsiness or insomnia
- 37. First drug forfilariasis caused by the nematodes Wuchereria bancrofti (90% cases) and Brugia malayi.-1948 Mf Adults Wuchereria bancrofti Peripheral blood (2mg/kg TDS in 7 days) (Transudates and nodules) Slow macrofilaricidal - prolonged treatment Brugia malayi. Loa loa and Onchocerca volvulus
- 38. MOA • Alteration of organelle membranesof the Mf promoting celL death • Dislodgement d/t alteration in muscular activity of Mf and adult worms • Make them susceptible to host defense mechanism PK • Well absorbed ,better with meals • Distributed all over the body (V = 3–5 L/kg) • Metabolized in liver • Excreted in urine. • Plasma t½ of usual clinical doses is 4–12 hours A/E • Nausea, loss of appetite, headache, weakness and dizziness • Febrile reaction with rash, pruritus, enlargement of lymph nodes, bronchospasm and fall in BP - due to mass destruction of Mf and adult worms. • Leukocytosis and mild albuminuria MAZZOTTI’S REACTION Minimized by starting with a low dose (0.5 mg/kg). temporarily withheld Antihistaminics and/or corticosteroids given.
- 39. Filariasis: - firstline drug: •2 mg/kg TDS - rapid symptomatic relief; Mf disappear from blood and patient becomes noninfective to mosquitoes in 7 days •Adult worm survives in the lymphatics and gives rise to intermittent microfilaraemia and symptoms. •Radical cure- Prolonged treatment with different schedules •A total dose of 72–126 mg/kg spread over 12 days to 3 weeks •More than one course may be needed with a gap of 3–4 weeks Elephantiasis due to chronic lymphatic obstruction un -affected by because fibrosis of lymphatics is irreversible. Tropical pulmonary eosinophilia 2–4 mg/kg TDS) for 2–3 weeks Loa loa and O. volvulus Give small (25–50 mg) test dose initially which avoids severe reaction Yearly treatment with a combination of DEC (6 mg/kg) and albendazole (400 mg) single dose on mass scale
- 40. Extremely potent semisyntheticderivative of the antinematodal principle obtained from Streptomyces avermitilis. Microfilaricidal but not macrofilaricidal Onchocerciasis and Strongyloidosis W.bancrofti and brugian filaria Cutaneous larva migrans Ascariasis Enterobius and Trichuris Moderately effective
- 41. Flukes and tapeworms-unaffected by ivermectin 2. Potentiation of GABAergic transmission in the worm Low affinity for mammalian GABA receptors and its exclusion from the brain, by P-glycoprotein mediated efflux at the blood-brain barrier. Opens glutamate gated Cl¯ channel Hyperpolarisation Tonic paralysis
- 42. PK • Well absorbed orally, •Widely distributed in the body, but does not enter CNS, • Sequestrated in liver and fat • CYP3A4 • Terminal t½ of 48–60 hours. USES • Filariasis10- 15mg+ 400mg Albendazole - • Strongyloidosis- 0.2 mg/kg • Onchocerciasis ,River blindness– One dose every 6-12 months replaced DEC • Only Mf • Scabies and Pediculosis- 0.2 mg/kg A/E • Mild—pruritus, giddiness, nausea, abdominal pain, constipation, lethargy and transient ECG changes • Mazzottis’s reaction due to degeneration products of the Mf • Fever, headache, dizziness, somnolence, and hypotension) Diethylcarbamazine- accelerate blindness and cause severe Mazzotti reactions
- 46. Ca2+ channel sensitive to praziquantel Leakage ofintracellular calcium from the membranes Contracture and paralysis Dislodgement from tissues and veins Vacuolization of the tegument Release of the contents of tapeworms and flukes Destruction by immune mechanisms of the host
- 47. PK USES A/E •Rapidly absorbedfrom intestines;absorptio n is enhanced if it is ingested with food. •High first pass metabolism in liver •Induction of metabolism –by Dexamethasone, Phenytoin – Therapeutic failure •Crosses BBB •Excreted in urine •Plasma t½ is short (1.5 hours). 1. Schistosomes: All 3 species can be treated with 40–75 mg/kg given once 2. All flukes except Fasciola hepatica- 75 mg/kg •No systemic toxicity. •Nausea and abdominal pain- bitter taste •Headache, dizziness and sedation. •Reaction to destruction by parasites - Itching, urticaria, rashes, fever and bodyache
- 49. Narrow spectrum benzimidazole DOCfor fascioliasis( 10mg /kg single dose) Paragonimus skrjasbini(10mg/kg orally daily for 3 days) No significant side effects
- 50. Metrifonate Organophosphorous compound Alternative forS.hematobium Not effective against S.mansoni,S.japonicum Dose 7.5-10 mg TDS at intervals of 2 weeks A/E Cholinergic side effects C/I Pregnancy, Recent insecticides exposure, with Succinyl choline
- 51. Oxamniquine S.Mansoni Not effective againstS.hematobium,S.japonicum A/E Drowsiness,Dizziness,Seizures Pruritus, Urticaria Dose 15-20mg/kg single dose C/I Pregnancy,Epilepsy
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- 54. Infestations due toTaenia saginata,T. solium, Diphyllobothrium latum and Hymenolepis nana, as well as pin worm MOA – Inhibition of mitochondrial phosphorylation of adenosine diphosphate (ADP) in the parasite ATP is not generated lethal for the cestode’s scolex and segments but not for the ova. Inhibition of Anaerobic metabolism Partly digested in intestine T.Solium Ova released from digestion develops into larvae VISCERAL CYSTICERCOSIS
- 55. TAPEWORM - 0.5g tab After a light breakfast, 2 tablets are to be chewed and swallowed with water, followed by another 2 tablets after 1 hr (total 2 g); Saline purge is given 2 hours after the later dose to wash off the worm. The scolex should be searched in the stools to be sure that the worm will not grow again H. nana 2 g dose is repeated daily for 5 days. - This is needed because cysticerci of H. nana (which are not affected by niclosamide) develop in the jejunal villi of the same host and worms appear in the intestinal lumen after 4 days. Praziquantel is now preferred due to single dose treatment. A/E •No systemic toxicity occurs. •Minor abdominal symptoms •Malaise, pruritus and light headedness are rare.
- 56. Taeniasis- T. saginata, T.solium •90–100% cure •10 mg/kg single dose in the morning. • It is especially valuable in case of T. solium, because it kills the tapeworm larvae within the cysts and there are no chances of systemic cysticercosis developing. H. nana, D. latum: •15–25 mg/kg single dose in the morning.,better than Niclosamide Neurocysticercosis:. 50 mg/kg daily in 3 divided doses for 15–30 days kills the larvae lodged in brain and other tissues
- 57. Primary therapeutic application-treatment of cestodal infestations, 1) Hydatid disease- 400 mg BD for 4 weeks, repeat after 2 weeks (if required), up to 3 courses.- the preferred treatment given before and after surgery as well as to inoperable cases (3 months)- has a risk of hepatotoxicity and, rarely, agranulocytosis or pancytopenia. 2) Neurocysticercosis- anthelmintic of choice Usually 8–15 days course of 400 mg BD (15 mg/kg/day) 3) Cysticercosis of other tissues (muscles, subcutaneous area) also responds, but no drug should be given for ocular cysticercosis—blindness can occur due to the reaction. A/E is associated with inflammatory responses to dying parasites in the CNS, including headache,vomiting, fever, and seizures. 4) Tapeworms - 400 mg daily for 3 consecutive days
- 58. Hydatid disease: 200–400mg BD or TDS for 3–4 weeks; less effective than albendazole.
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- 60. NEMATODES Ascaris ( roundworm) Albendazole Ankylostoma (hookworm) Albendazole . Trichura (whipworm) Albendazole Enterobius ( pinworm) Mebendazole Strongyloides( thread worm) Ivermectin Trichinella Albendazole/Mebendazole Onchocerca Ivermectin Cutaneous larva migrans Visceral larva migrans Albendazole Ivermectin CESTODES Taenia saginata, solium, Diphyllobothriasis Praziquantel TREMATODES S hematobium C.Sinensis P . Westermani Praziquantel
- 61. What is thediagnosis and pharmacological management? The same patient developed fever, urticaria, swollen and tender lymph nodes tachycardia, hypotension, and abdominal pain within seven days of treatment .. A.What is this known as ? B. Why this has happened and how would you manage this patient
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Editor's Notes
- #17 Upto 75% cure has been reported in tapeworms, but H. nana is relatively insensitive Prolonged treatment has been shown to cause regression of hydatid cysts in the liver. Treatment after resection of the cyst may prevent its regrowth
- #18 The immobilizing and lethal action of mebendazole on worms is rather slow: takes 2–3 days to develop.
- #20 Hookworm Whipworm Upto 7 day treatment may be needed in heavy trichuriasis Pin worm (Enterobius) 100 mg single dose, repeated after 2–3 weeks (to kill the ova that have developed later). Strict hygienic measures and simultaneous treatment of all children in the family or class is advocated to cut down autoinfection and person to person infection. This holds true of enterobiasis, irrespective of drug used. Trichinosis: 200 mg BD for 4 days; less effective than albendazole. Hydatid disease: 200–400 mg BD or TDS for 3–4 weeks; less effective than albendazole. Guinea worm: Mebendazole is an alternative drug to metronidazole for facilitating extraction of the worm, when the latter cannot be given. Mebendazole is one of the preferred drugs for treatment of multiple infestations and is more effective than albendazole in trichuriasis. It has also been used for mass treatment, but need for multiple doses is a drawback
- #22 probably due to starvation of the parasite and their slow death.
- #24 Three day treatment has been found necessary for tapeworms including H. nana. Results in hydatid disease and hookworm have been superior to mebendazole. Albendazole has weak microfilaricidal action, kills cysticerci, hydatid larvae, ova of ascaris/ hookworm and is also effective in cutaneous larva migrans.
- #25 (this may help in treating neurocysticercosis and hydatid disease).
- #26 , while for cysticercosis, hydatid and cutaneous larva migrans it should be given with a fatty meal. Tapeworms and Efficacy in strongyloidosis
- #30 Thiabendazole has gone out of use, due to the availability of better tolerated mebendazole and albendazole.
- #34 Introduced in 1950, it is a highly active drug against However, because of the availability at more convenient and better tolerated albendazole/mebendazole it is now considered a second choice drug. Cholinergic receptors in mammalian skeletal muscle have very low affinity for pyrantel.
- #37 Tetramisole was developed in the late 1960s. It is racemic; its levo isomer (levamisole) was found to be more active and is preferred now
- #39 This is usually mild, but may be severe
- #42 glutamate-gated chloride channel receptors. Chloride influx is enhanced, and hyperpolarization occurs, resulting in paralysis and death of the worm. in invertebrates. Such channels are not involved in the motor control
- #55 A laxative is administered prior to oral administration to purge the bowel of all dead segments and to enhance digestion and liberation of the ova. Alcohol should be avoided within 1 day of niclosamide