Dr. Mohd Ashraf AlamDepartment of Pharmacology

JNMC. AMU

Pharmacotherapy of Anthelminthic Drugs

Epidemiology

Distribution of soil-transmitted helminthiases and proportion of children (aged1-14 years) in each endemic country requiring preventive chemotherapy for the diseases, 2011

• There are four main nematode species of human soil-transmitted

helminth (STH) infections, also known as geohelminths.

• Ascaris lumbricoides (roundworm), Trichuris trichiura (whipworm),

Ancylostoma duodenale and Necator americanus (hookworms). 

• May be Vermicide – Drugs that kill wormsVermifuge – expel infesting helminths

Peristaltic movement of IntestineCathartic and purgative action

Ideal anthelmintics:Orally effectiveEffective in single doseInexpensiveWide safety of margin with highest toxicity to worms, but lesser toxic to the

host

Anthelminthic Drugs

• Benzimidazoles (BZ) : Albendazole, Mebendazole, • Diethylcarbamazine (DEC)• Ivermectin• Praziquantel• Niclosamide• Piperazine• Praziquentel• Metrifonate

ANTHELMINTHIC DRUGS

Benzimidazoles (BZ)• MOA

• The primary mechanism of action of BZ is thought to be inhibition of

microtubule polymerization by binding to β –tubulin

• Inhibition of mitochondrial fumarate reductase, reduced glucose

transport, and uncoupling of oxidative phosphorylation

• Albendazole is DOC

• Cysticercosis: Taenia solium

• Cystic hydatid disease: Echinococcus granulosus

• single dose combination with ivermectin or DEC, it has shown

additive effect in the control of lymphatic filariasis and related

tissue filarial infections

• Albendazole is superior to mebendazole in curing hookworm and

trichuriasis infections in children

• albendazole is more effective than mebendazole against

strongyloidis.

• superior to mebendazole against all tissue-dwelling helminths

due to its active metabolite albendazole sulfoxide.

• Albendazole is highly effective against cutaneous larva migrans

• mebendazole and albendazole are highly effective in treating most

of the major STH infections (ascariasis, enterobiasis, trichuriasis,

and hookworm)

• both larval and adult stages of nematodes

• ovicidal for Ascaris and Trichuris

Dose of Albendazole

• STH (enterobiasis, ascariasis, trichuriasis, and hookworm), :single

oral 400-mg dose in adults and children >2 years of age

• Between 12 and 24 months, the WHO recommends a reduced dose

of 200 mg

• For heavy ascariasis infection the dose can be repeated for 2-3 days

• Echinococcus granulosus: Cystic Hydatid Disease

• 400 mg given BD(for children, 15 mg/kg per day with a

maximum of 800 mg) for 1-6 months.

• drug provides only a modest cure rate when used alone

• the only drug available with useful activity against alveolar

echinococcosis caused by E. multilocularis

• Neurocysticercosis: T.solium

• 400 mg given BD for 8-30 days (for children, 15 mg/kg per day

with a maximum of 800 mg)

Dose of Mebendazole

Enterobiasis, a single 100-mg tablet; a second dose given after 2

weeks.

Ascariasis, Trichuriasis, Hookworm infections:100 mg BD for 3

days (or a single 500-mg tablet administered once).

The 3-day mebendazole regimen is more effective than single

doses of either mebendazole (500 mg)

• Transient mild GI symptoms (epigastric pain, diarrhea, nausea, and vomiting) occur

in ~1% of treated individuals with Albendazole

• In long-term therapy of cystic hydatid disease and neurocysticercosis most common

side effect is liver dysfunction, generally manifested by an increase in serum

transaminase levels and rarely jaundice

• Therefore, liver function tests should be monitored

• Albendazole is teratogenic and embryotoxic in animals, and it should not be given to

pregnant women

• The safety of albendazole in children < 2 years of age has not been established.

Adverse Effects

• Mebendazole does not cause significant systemic toxicity due to low

Bioavailability

• Transient symptoms of abdominal pain, distention, and diarrhea have

occurred in cases of massive infestation and expulsion of GI worms

• Mebendazole is a potent embryo toxin and teratogen in laboratory

animals but no evidence for teratogenicity in humans has been

reported.

• mebendazole should not be given to pregnant women or to children

<2 years of age as a precautionary measure.

• Excluding thiabendazole, the BZs have excellent safety profiles

• Side effects frequently encountered with therapeutic doses include

anorexia, nausea, vomiting, and dizziness.

• Less frequently, diarrhea, fatigue, drowsiness, giddiness, or

headache occur

• Thiabendazole has hepatotoxic potential.

• Thiabendazole in pregnant women have not been studied

adequately.

• MOA

• The mechanism of action of DEC against susceptible filarial

species is not well understood, but the drug appears to exert a

direct effect on W. bancrofti microfilariae by causing organelle

damage and apoptosis ,

• It has also been proposed that DEC compromises intracellular

processing and transport of certain macromolecules to the plasma

membrane

Diethylcarbamazine (DEC)

• Diethylcarbamazine (DEC) is a first-line agent for control and

treatment of lymphatic filariasis caused by Wuchereria bancrofti and

Brugia malayi

• DEC is also the drug of choice for treatment of loasis

• Dose

• The standard regimen for the treatment of LF traditionally has been a 2

– 3 weeks, (2 mg/kg TDS) course of DEC.

• Repeat treatment is recommended if microfilariae remain in the

circulation or if motile adult worms remain visible on the ultrasound

• DEC is contraindicated for the treatment of onchocerciasis

because it causes severe reactions related to microfilarial

destruction, including worsening ocular lesions

• Dose in Loasis

Treatment is initiated with test doses of 50 mg (1 mg/kg in

children) daily for 2-3 days, to a maximal tolerated daily doses of 9

mg/kg in three doses for a total of 2-3 weeks.

Albendazole may be useful in patients who either fail therapy with

DEC or who cannot tolerate the drug

• At therapeutic dose these reactions are rare and include anorexia, nausea, headache, and, vomiting at high doses.• Major adverse effects result directly or indirectly from the host in

response to destruction of parasites, primarily microfilariae.• It can be lymphangitis, swelling, and lymphoid abscesses in

filariasis • In heavy L. loa infections, including retinal hemorrhages and

severe encephalopathy• the Mazzotti reaction: onchocerciasis on taking 1st dose.• C/I :DEC should be avoided where onchocerciasis or loiasis is

endemic• Safe in Pregnancy

ADR

IvermectinMOAThe drug shows useful activity against most Nematodes that infect humans but

not against trematodes and cystodes

Ivermectin TargetsLigand -gated Cl– channels

Chloride ion influx enhanced

Hyper polarization occurs

Paralysis of the worm

• Onchocerciasissingle oral dose (150 to 200 g/kg) given every 6-12 months is DOCIn adults and children more than 5years.

• Lymphatic FilariasisSingle annual dose (400 μg/kg) for mass chemoprophylaxis.Duration of treatment to reduce the filarial load by 65% is around 6 years.• single annual dose of ivermectin (200 μg/kg) + single annual dose of

albendazole (400 mg) . Treatment duration is 5 years

Therapeutic Uses

• Strongyloidiasissingle dose of 150 to 200 μg/kg is DOC. 2nd Dose is administered after a week.• Cutaneous larva migrans single 200 μg/kg oral dose is DOC

• Ivermectin is well tolerated by uninfected humans• Mazzotti-like reaction in filarial infection• Rarely high fever, tachycardia, hypotension, prostration,

dizziness, headache, myalgia, arthralgia, diarrhea

• C/I in disease which disrupts blood brain barrier(e.g., African trypanosomiasis and meningitis).

• Not approved in pregnancy and children less than 5years of age

Side Effects

• The drug shows useful activity against most cestodes and trematodes that infect humans but not nematodes• MOAIt causes leakage of intracellular Ca2+ from Membranes

contracture and Paralysis

Active against adult, as well as larval stage of Tapeworms

Praziquantel

• DOC for Schistosomiasis• Dose is single oral dose of 40 mg/kg or three doses of 20 mg/kg

each given 4 hours apart produce cure rate of 70-90%

• For liver flukes Clonorchis sinensis and Opisthorchis viverrini the dose is 25 mg/kg TDS taken 4-8 hours apart.• For lung fluke, Paragonimus westermani same dose is repeated

for 2 days• The liver fluke Fasciola hepatica is resistant to praziquantel

Therapeutic Uses

• Hymenolepis nana: single oral dose of 25 mg/kg • Diphyllobothrium latum, Taenia saginata, or T. solium :10 to 20 mg/kg • Neuro cysticercosis : 50 mg/kg/day in 3 divided dose for 15 days

• ADR

• Abdominal discomfort, particularly pain and nausea, diarrhea, headache,

dizziness, and drowsiness

• In neurocysticercosis, inflammatory reactions to praziquantel may

produce seizures, mental changes

• Praziquantel is considered safe in children >4 years of age

• High doses of praziquantel increase abortion rates in rats but its

teratogenicity has not been reported in humans

• Praziquantel is contraindicated in ocular cysticercosis

• MOA

• Inhibit oxidative phosphorylation in mitochondria and interfere with

anaerobic generation of ATP by tapeworm.

• Injured tapeworm are digested in intestine.

• Highly effective against cestodes T.solium , T.saginata, D.latum,

H.nana..

• Not ovicidal

Niclosamide

• No systemic toxicity occurs as GI absorption is minimal.• Well tolerated .

• Safe in Pregnancy and Patients with Poor Health.

DoseTapeworm : 2g in 2 divided dose 1 hour apart

ADR

• Pyrantel PamoateMOA

Causes activation of Nicotinic Cholinergic receptors in worms

Persistent Depolarization

Contracture and Spastic Paralysis

Expulsion of worms

Adverse Effects • Occasional GI symtoms are reported.

• Safety in Pregnancy And In Children Less than 2 years is not established.

Use• Ascaris , Ancyclostoma, Entrobius : 10mg/kg single dose.• Necator , Strongyloides : 3 day course recommended.

• Effective Against Ascaris And Entrobius• MOA Piperazine Targets GABA-gated Cl– channels in Ascaris

Chloride ion influx enhanced

Hyper polarization occurs

Paralysis of the worm

Piperazine

• Adverse Effects• Its safe and well tolerated • Nausea, vomiting and Abdominal Discomfort may be seen.• Toxic dose produce convulsions.

• C/I in epileptics and renal insufficiency• Safe in Pregnancy

• Dose• Roundworm : 4g OD for 2 days.(0.75g /year for Children)• Pinworm :50 mg/ kg (max 2g) OD for 7 days.

Metrifonate

• an organophosphorus compound • Metrifonate is a prodrug

• at physiological pH, it is converted non enzymatically to dichlorvos

(2,2-dichlorovinyl dimethyl phosphate, DDVP), a potent

cholinesterase inhibitor

• Used especially for treatment of Schistosoma haematobium

• Dose : single oral dose 10mg/kg TDS , repeated after 2 weeks