y can be round bodied worms (Nemathelminths) or flat bodied (Platyhelminths)
Nemathelminths (nematodes)
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Platyhelminths (two types – flukes, tape worms)
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1. Round worms (Ascaris lumbricoides)
2. Hook worms (Nector americanus or Ancylostoma duodenale)
3. Whip worms (Trichuris trichiura)
4. Thread worms (Strongyloides stercoralis)
5. Pin worms (Enterobius vermicularis)
6. Filarias (Wuchereria bancrofit or Brugia malayi)
7. Onchocerciasis (Onchocerca volvulus)
8. Guinea worms (Dracunculus medinensis)
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1. Trematodes (flukes)
a. Blood flukes (Schistosomiasis or bilharziasis)
b. Liver flukes (Clonorchiasis)
c. Intestinal flukes (Fasciolopsiasis)
d. Lung flukes (Paragonimiasis)
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2. Cestodes (tapeworms)
a. Beef tape worm (Taenia solium)
b. Fish tape worm (Diphylloborthrium)
c. Dwarf tape worm (Hymenolepis nana)
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§ Anthelmintics à drugs used as vermicide (kill) or vermifuge (expel) to the infesting helminth
§ They attack only parasite cell not mammalian cell à so they have selective toxicity to the helminthes
§ Their MOA is by interfering with
o Neuromuscular functions
o Microtubular functions
o Ca+2 permeability
o Energy metabolism
Mechanism of Action of Different Anthelmintics
Against “Nematodes”
§ The
locomotor muscles of nematodes have both cholinergic & GABAergic
innervations & their neuromuscular junction has both excitatory
cholinergic-nicotinic (NN) & inhibitory GABAergic receptors
Pyrantel pamoate
§ It is a NN-receptor agonist & causes release of ACh by inhibition of acetylcholinesterase à it produces depolarizing neuromuscular blockade à affected helminthes are unable to maintain their attachment to the intestinal lumen à expelled in the feces.
Levamisole
§ It is also a NN-receptor agonist à causes a depolarizing block at the nematode’s neuromuscular junction
Piperazine
§ It is a GABA receptor agonist & activates GABA-gated Cl- channel in nematode muscles à flaccid paralysis of nematode results due to Cl- dependent hyperpolarisation à paralysed worms are expelled alive
Ivermectin
§ It
also activates Cl- channels but it primarily acts on nematode specific
glutamate gated Cl- channels which are also inhibitory due to subsequent
hyperpolarisation
§ These
glutamate-mediated voltage gated Cl- channels are found on the
pharyngeal muscles of all nematodes only & are physiologically
related to the vertebrate GABA-gated Cl- channels
Diethylcarbamazine (DEC)
§ It is a piperazine derivative
§ It alters the micro-filarial membrane surface characteristics à they are subsequently phagocytosed by tissue fixed monocytes (not by circulating phagocytes)
§ It also hyperpolarizes the worm’s musculature (due to piperazine moiety) à so that they are expelled
§ It also blocks PGs à resulting in capillary vasoconstriction & impairment of the passage of microfilariae
Against “Trematodes”
Metrifonate
§ It is an organophosphorus compound
§ MOA resembles with Pyrantel pamoate
§ Its active metabolite “Dichlorvos” à inactivates acetylcholinesterase & potentiates depolarizing neuromuscular blockade of Blood fluke
Oxamniquine
§ It acts by intercalation in the parasitic DNA à leading to the death of schistosome ß by blocking its nucleic acid & protein synthesis
§ The fluke probably first esterfies oxamniquine to produce a reactive metabolite that alkylates parasite DNA
Bithionol
§ It uncouples parasite specific (fumarate reductase-mediated) oxidative phosphorylation à blocks ATP synthesis à it inhibits the energy derived by the helminth from the anaerobic metabolism
Against “Cestodes”
Niclosamide
§ It appears to uncouple oxidative phosphorylation in adult cystode à its results in expulsion of dead worm in the feces
§ It inhibits the anaerobic incorporation of energy rich inorganic phosphates into ATP, which is determinal to the parasite
Against “Trematodes as well as Cestodes”
Praziquantel
§ It causes influx of Ca+2 from endogenous stores of the cestodes à resulting in intense contractions & subsequent expulsion of the worm from GIT
§ In Schistosomes (flukes) à praziquantel-induced influx of Ca+2 damages the tegument, causing vacuolations (holes) à which exposes the hidden parasite antigens
§ The antibodies, in the host, then bind to these antigens & destroy them by phagocytosis
“Broad Spectrum” Anthelmintics
§ These are benzimidazole group of anthelmintics [ Thiabendazole, Mebendazole, Albendazole, Triclabendazole ]
§ All share a common mechanism of action
§ They have different mode of action
§ Cytoskeletal structures of helminthes include microfilaments, microtubule & β-tubulins
§ Under normal conditions,
o microtubule assembly is dependent on β-tubulin function
o β-tubulin dimmers are continually being polymerized from one end & then depolymerised at the other end of the microtubels
§ Benzimidazoles
bind to β-tubulins & prevent their assembly, i.e., polymerization,
resulting in breakdown of microtubules with selective & irreversible
inhibitionof glucose uptake.
§ The end result à depletion of parasite’s glycogen stores à reduced formation of ATP à disruption of metabolic pathways à ultimately parasitic death
§ These drugs bind to parasite β-tubulin with much higher affinity à
serum glucose concentration of the human host is not affected &
hence the selective toxicity of these drugs to helminthes only
Details of Individual drugs
Albendazole
§ It is a broad spectrum oral anthelmintic
§ Its oral absorption is variable à so its recommended to with fatty meals à absorption increases by 5 folds
§ Its rapidly metabolized in liver to an active sulfoxide metabolite à which is 70% protein bound (distributes in bile, CSF, hydatid cysts)
§ Elimination half life is 8-12 hrs & excreted in urine
Clinical Use
§ Its is particularly used against Intestinal Nematodes, Cestodes and Liver fluke
§ Its drug of choice against Common round worm, Whip worm, Hook worms
[Dose for adults and children above 2 yrs : 400 mg orally as a single
dose at night , Dose for children below 2 yrs: 200mg OD; in heavy
infestations dose may be repeated for 3 days]
§ It is also preferred drug to treat Cutaneous larva migrans [400 mg OD for 5 days] & Visceral larva migrans [400mg BD for 28 days]
§ It is drug of choice for Cysticercosis [pork warm – larva stage], Hydatid disease [Dose for both the conditions: 400mg BD for 28 days with fatty meals]
§ Normally for Cysticercosis corticosteroids are given along with albendazole à to prevent inflammation caused by the dying organism
§ For Hydatid disease à Albendazole is used along with praziquantel (?)
§ Its alternative for the treatment of Thread worm [400 mg OD for 3 days], Pin worm [400mg OD to be repeated after 2 weeks], Liver flukes [400mg BD for 7 days]
§ Its given on empty stomach when used against intraluminal worms but with a fatty meals used against tissue parasites (?)
§ Albendazole + DEC or Ivermectin is a synergistic combination for treating or controlling lymphatic filariasis
Adverse Effects
§ It is well tolerated & side effects are rare for a period of 3-5 days
§ In case of Cysticerosis & Hydatid diseases à up to 1 month à no side effects seen
§ If it is used for 3 months à epigastric distress, headache, alopecia, fatigue, lassitude, insominia, transient aminotransferase enzyme elevation
§ Its teratogenic à long term use in pregnancy should be avoided [Do not take when pregnant, and do not become pregnant for one month after taking this drug]
Mebendazole
§ Its having wide spectrum of anthelmintic activity
§ Absorption increases with fatty meals à its 90% protein bound
§ Its extensively metabolized à excreted in urine (decarboxylated metabolized) & bile (absorbed unchanged drug)
§ Half life is 2-6 hrs
Clinical Uses
§ It
is still considered a drug of choice for the treatment of Round worms,
Whip worm, Hook worm [dose: 100mg BD for 3 consecutive days]
§ It
provides 95-100% cure rate in Pin worm infestations [dose: 100 mg OD
repeated after 2 weeks (to eradicate ova that have developed later)]
§ Its used in mixed infections (ascaris + hook worm or ascaris + hook worm + whip worm)
§ It
is alternative drug for the treatment of Trichinosis [dose: 200mg TDS
initially, increasing over 3 days to 400mg TDS & continued for next
10 days], Intestinal capillariasis [dose: 200mg BD for 21 days],
Visceral larva migrans [dose:100mg TDS for 5days], Beef tape worm [dose:
200mg BD for 4 days
§ Metronidazole tablets are to be chewed before swallowing
Adverse Effects
§ Short-term therapy with mebendazole is nearly free of side effects
§ Abdominal discomfort, nausea, vomiting & diarrhea have been observed
§ With higher doses – rash, urticaria, & elevation of aminotransferase enzymes
§ It is contraindicated in patients of liver cirrhosis & pregnancy
Levamisole
§ It has a restricted use
§ It is rapidly absorbed from the GIT & extensively metabolized in liver; Plasma half life – 3-4hrs
Clinical Uses
§ Its
used in Ascariasis [dose: 50 mg for children having 10-20 kg body
weight, 100mg for children having 21-40kg body weight, 150 mg for
adults]
§ Its
used in Hook worm infestations or mixed round worm – Hook worm
infestations [dose: 300 mg Orally as a single dose over 2 days for
adults, 6mg/kg orally once for 2 days in children]
§ It is also used as immunestimulant as it restores depressed T-cell functions [dose: 150mg OD for 2 consecutive days in a week]
§ Its also used for mouth ulceration in initial stages [dose: 150 mg daily in divided doses given for 3 days]
§ It is also used as an adjunct drug in malignancy
§ Along with Fluorouracil, it inhibits the recurrences of Colorectal cancer following resection of tumors
Adverse Effects
§ Its well tolerated and side effects are limited to nausea, vomiting, abdominal discomfort, headache
§ Long
term Use – influenza like syndrome, hypersensitivity, arthralgia,
muscle pain, abnormal taste in mouth, rarely thrombocytopenia
Metrifonate
§ Its an organophosphorus compound and its effective only in Bilharziasis
§ Its orally absorbed and undergoes non-enzymatic to yield an active metabolite Dichlorvos
§ Both the drug & its active metabolite are widely distributed to the tissues
§ Plasma half life of Metrifonate is 2hrs but the drug & metabolite completely eliminated in 24-48 hrs
§ Its well tolerated but cause cholinergic side effects like diarrhea, tremors, nausea, vomiting, bronchospasm, sweating
§ Its contraindicated in pregnancy, recent insecticide exposure, with depolarizing neuromuscular blocker
Niclosamide
§ It is used for the treatment of most cestodes (tape worm) infection
§ It is not absorbed from the GIT à high conc in lumen achieved
§ The drug affects the scolex & proximal segments of most cestodes à resulting in their detachment from the intestinal wall & evacuation by the normal peristaltic action
§ The drug is not Ovicidal
§ The use of this drug declined due to availability of better drugs
§ No serious side effects observed except for abdominal discomfort, nausea, loose stools
Praziquantel
§ Given through oral route – 80% absorption
§ Its 80% bound to plasma proteins
§ It undergoes 1st pass in the liver à converted to inactive hydroxylated metabolites à excretion is through kidneys (80%), bile (20%)
§ Plasma half life is 1-3 hrs
§ Plasma concentration increases à when taken along with a high carbohydrate meal (?)
§ Bioavailability is reduced with concomitant use of phenytoin, carbamazepine, dexamethasone (?)
Clinical Uses
§ It is a drug of choice for all sorts of Schistosomiasis à possessing activity against male & female adults & immature stages
§ For S.mansoni & S.haematobium à dose: 20 mg/kg orally BD , For S.japonicum & S.mekongi à dose: 20mg/kg TDS
§ It is very effective against other flukes also [dose: 75 mg/kg once or in 2 divided doses for 1 or 2 days] except for F.hepatica
§ It is also used effectively for Tape worm infestations
§ For T.solium & T.saginata [dose: single dose of 10mg/kg in the morning], for D.latum & H.nana [dose: 15-25 mg/kg in the morning]
§ It is also used to treat Neurocysticerosis apart from Albendazole [dose: 50mg/kg daily in 3 divided doses for 15 days à kills the larve lodged in brain & other tissues]
§ Corticosteroids reduce the bioavailability of praziquantel à they should not be combined
Adverse Effects
§ Includes
drowsiness, dizziness, headache, nausea, vomiting, abdominal pains,
urticaria, skin rashes with eosinophilia (due to release of proteins
from dying worms)
§ Its not safer for children below 5 yrs
§ It is contraindicated in ocular cysticerosis à because of the risk of severe eye damage resulting from occlusion due to dead parasites
Pyrantel Pamoate & Oxantel Pamoate
§ Pyrantel pamoate is less absorbed from GIT à high levels are achieved in the intestinal tract à it is active against luminal helminthes
§ Half of the unchanged drug is excreted in feces
Clinical Uses
§ Pyrantel pamoate is active against Nematodes: round worms, hook worms, pin worms [dose: 10mg/kg orally as a single dose]
§ For pin worm à dose is repeated after 2 weeks
§ For heavy infestations with N.americanus à 3 days course is needed
§ Pyrantel is not active against whipworms à but Oxantel is active
§ So combination of these two drugs is available à to achieve a broad spectrum nematodal activity
Adverse Effects
§ It has no major adverse effects
§ It has headache, dizziness, drowsiness
§ It is not safer in pregnancy and children below 2 yrs
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