Antiparasitic Drugs

8/11/2019 Antiparasitic Drugs

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Antiparasitic drugs


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Male fern (Dryopterisfilix-mas(L.) Schott)


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Anthelminthic Drugs

Vermicide- kill

Vermifuge- expell Unlike protozoa, helminths are large and have complex

cellular structures


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Developing countries

Most of the protozoal infections are due to

unhygienic conditions. Harm host by

depriving him of food,

blood loss, injury to organs,

toxin,

obstruction of intestine or lymphatics Rarely fatal

Resistance no big issue


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Anthelminthic drugs

Three major groups of helminths (worms)areNematodes

Trematodes

Cestodes


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Nematodes :

Round worm ---Ascariasis

Hook worm --- Ancylostoma duodenale, Nectar Americans

Pin worm --- Enterobiasis

Thread worm--- Strongyloides Whipworm --- Trichuris trichuria

Nematodes :

Trichinosis Trichinella spiralis

Filariasis Wucheria bancrofti

Onchocerciasis (River blindness) -Onchocerca volvulus

TREMATODES ( FLUKES ) :

Chinese liver flukeClonorchis sinesis

Lung fluke---- Paragonimus westermani

Schistosomiasis

Schistosoma spCestodes Tape worm

Beef tape wormTaenia saginata

Pork tape wormTaenia solium

Fish tape wormDiphyllobothrium latum

Dog tape wormEchinococcus granulosis


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Modes of Transmission Four main mechanisms for parasitic transfer:

Ingestion of eggs from the

fecal material of an infected

individual Ascaris lumbricoides

The larva of the parasite can burrow into

the skin of a person Schistosomes

The larva of the parasite can

move from person to personthrough an insect vector

Trypanosomes

Plasmodia

Sexual transmission

Trichomonas vaginalis


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Mode of worm infestation

A. In the hosts gut:

Round worms (nematodes)

Tapeworms (cestodes)B. In the tissues of hosts:

Schistosomiasis (flukes: bilharzias): S.

mansoni, etc. Tissue round worms: filiareae, dranculus

medinensis (guinea worm)


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Anthelminthic drugs

Drugs for helminths

Nematodes :Albendazole, Mebendazole,Pyrantel pamoate, Diethylcarbamazine,Ivermectin

Trematodes :Praziquantel,metrifonate,bithionol, emetine, dehydroemetine

Cestodes :Niclosamide, Praziquantel,Albendazole


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Anti-helminthic drugs

Benzimidazole :

Thiabendazole, Albendazole & Mebendazole

Effective against wide spectrum ofnematodes

It acts by binding and interfering the

assembly of microtubules It also decreases the glucose uptake


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Inhibits the polymerization of tubulin into microtubulesThis inhibition prevents cellular division and the absorption of

glucose in its intestines


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Thiobendazole

First benzimidazole

Effective for all species of nematodes infesting the g.i.t.-

roundworm, hookworm, Enterobius, Trichuris,

Strongyloides and Trichinella spiralis.

It also inhibits development of the eggs of worms and

kills larvae.

Thiabendazole affords symptomatic relief in cutaneous

larva migrans and skeletal muscle symptoms produced

by migration of Trichinella spiralis larvae to muscles.

HasAntiinflammatory, analgesic and antipyretic actions.

These may contribute to its effect in cutaneous larva

migrans and other inflammatory conditions produced by

larvae or worms in tissues.


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well absorbed from g.i.t., systemic adverse effects are

frequent and often interfere with normal activity

Nausea, vomiting, loss of appetite, headache, giddiness

are most common. It can impair alertness-driving andoperation of machinery should be prohibited.

Itching, abdominal pain, diarrhoea and a variety of other

symptoms are also produced.

Dose - 25 rng/kg/day in two divided doses taken aftermeals. Tablets must be chewed;

Uses

Because of frequent side effects and poor patient

acceptability, thiabendazole is used only when otherbetter tolerated drugs are ineffective.

Strongyloidosis

Cutaneous larva migrans


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Mebendazole congener of thiabendazole

it retained the broad-spectrum anthelmintic activity but notthe toxicity of its predecessor.

It has produced nearly 100% cure rate/ reduction in egg

count in roundworm, hookworm (both species), Enterobius

and Trichuris infestations, but is much less active on Strongyloides.

Upto 75% cure has been reported in tapeworms, but H.

nana is relatively insensitive.

It expelsTrichinella spiralis from intestines, but efficacy inkilling larvae that have migrated to muscles is uncertain.

Prolonged treatment has been shown to cause regression

of hydatid cysts in the liver. Treatment after resection of

the cyst may prevent its regrowth


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Mechanism of action

It acts probably by blocking glucose uptake in theparasite and depletion of its glycogen stores.

The site of action of mebendazole appears to be

the microtubular protein beta-tubulin' of theparasite.

It binds to beta-tubulin of susceptible worms with

high affinity and inhibits its polymerization.

Intracellular microtubules in the cells of the wormare gradually lost.

The immobilizing and lethal action of mebendazole

on worms is rather slow: takes 2-3 days to develop.


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p/k- Absorption of mebendazole from

intestines is minimal; 75-90% of an oral dose

is passed in the faeces. The fraction absorbedis excreted mainly as inactive metabolites in

urine/faeces.

s/e- Diarrhoea, nausea and abdominal pain.

Incidents of expulsion of Ascaris from mouth

or nose have occurred, probably due to

starvation of the parasite and their slow death.

High doses --Allergic reactions, loss of hairand granulocytopenia

Pregnancy- C/I


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Uses of mebendazole

The dose and duration of treatment is the same for

children above 2 years as for adults; 1/2 dose for

1-2 yr age.

Roundworm, Hookworm, Whipworm

100 mg twice a day for 3 consecutive days. No fasting,purging or any other preparation of the patients is needed.

Enterobius100 mg single dose.

Strict hygienic measures and simultaneous treatment of all

children in the family or class Trichinella spiralis: 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.


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Albendazole congener of mebendazole: retains the broad-spectrum

activity and excellent tolerability of its predecessor, and hasthe advantage of single dose administration

One dose treatment has produced cure rates in ascariasis,

hookworm (both species) and enterobiasis which are

comparable to 3 day treatment with mebendazole.

Results in trichuriasishave been inferior to mebendazole.

In strongyloidosis, more effective than mebendazole: a 3

day course has achieved nearly 50% cure, and a second

course repeated after 3 weeks cured practically all patients.

Three day treatment has been found necessary for

tapewormsincluding H. nana.


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Results in hydatiddisease and hookwormhave been

superior to mebendazole.

Albendazole has weak microfilaricidalaction, kills cysticerci,

hydatid larvae, ova of ascaris/hookworm and is alsoeffective in cutaneous larva migrans.

The mechanism of action is similar to that of mebendazole.

Absorption of albendazole after oral administration is

moderate, but inconsistent. It is enhanced when the drug istaken with fatty meal (may help in treating

neurocysticercosis and hydatid disease).

Active metabolite

albendazole exert antihelmintic activity in tissues as well. Albendazole is well tolerated; only gastrointestinal side

effects have been noted. Few patients have felt dizziness.

Prolonged use, as in hydatid or in cysticercosis, has caused

headache, fever, alopecia, jaundice and neutropenia


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No preparation or postdrug fasting/

purging is required.

For intestinal worms it should be given on

empty stomach,

while for cysticercosis, hydatid and

cutaneous larva migrans it should be given

with a fatty meal.


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Ascaris, hookworm, Enterobius and Trichuris: single

dose of 400 mg (for adults and children above 2 yrs, 200

mg for 1-2 yr age).

Tapeworms and 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.

Neurocysticercosis: Albendazole is the anthelmintic

of choice for the treatment of neurocysticercosis. Usually

8-15 days course of 400 mg BD (15 mg/kg/ day) is

employed. Cysticercosisof other tissues (muscles,

subcutaneous area) also responds, but no drug should

be given for ocular cysticercosis-blindness can occur

due to the reaction.


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Cutaneous larva migrans: Albendazole 400 mg

daily for 3 days is the drug of choice; kills larvae

and relieves symptoms. Hydatid disease: 400 mg BD for 4 weeks, repeat

after 2 weeks (if required), up to 3 courses. It is

the preferred treatment given before and after

surgery as well as to inoperable cases.

Filariasis: Added to diethylcarbamazine (DEC) or

ivermectin, albendazole has adjuvant value

C/I pregnancy


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Benzimidazole :

Albendazole and Mebendazole are poorlyabsorbed from GIT whereas thiabendazoleis well absorbed.

Albendazole and Mebendazole are well

tolerated , thiabendazole causeshallucinations

Mebendazole and Albendazole are used

to treat intestinal nematode infections Thiabendazole is preferred drug of choice

in cutaneous larva migrans.

Contraindicated in pregnancy


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Pyrantel Pamoate :

It acts as a depolarizing neuromuscular agent

persistent activation of nicotinic receptors -resulting in

persistent depolarizatio-- slowly developing contracture

and spastic paralysis. Worms are then expelled.

An anticholinesterase action.

Because piperazine causes hyperpolarization and flaccid

paralysis, it antagonizes the action of pyrantel.

Cholinergic receptors in mammalian skeletal muscle

have very low affinity for pyrantel.

Only 10-15% of an oral dose of pyrantel pamoate is

absorbed: this is partly metabolized and excreted in

urine


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Used to treat round worm, hook worm and pin

worm. Efficacy comparable to mebendazole.

Lower cure rates (about 60%) have beenobtained in case of Necator infestation. It is less

active against Strongyloides and inactive against

Trichuris and other worms.

g.i. symptoms,headache and dizziness isreported. It is tasteless, nonirritant; abnormal

migration of worms is not provoked.

Its safety in pregnant women and in childrenbelow 2 years has not been established.

For Ascaris, Ancylostoma and Enterobius: a

single dose of 10 mg/kg

No fasting, purging or other preparation needed.


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Piperazine

highly active drug against Ascaris and Enterobius

now considered a second choice drug

Piperazine causes hyperpolarization of Ascaris muscle by a

GABA agonistic action -- opening Cl- channels that causes

relaxation and depresses responsiveness to contractile

action of ACh. Flaccid paralysis

worms are expelled alive

often a purgative (senna) is given with it, but is not

necessary. No fasting or patient preparation is required.

Piperazine does not excite Ascaris to abnormal migration.

It does not affect neuromuscular transmission in man.


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safe and well tolerated.

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, but is safe in the pregnant.

4 gm OD for 2 days. Intestinal obstruction due to roundworm.


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Levamisole, Tetramisole

use is restricted to ascariasis andancylostomiasis, because action on other worms

is poor.

The ganglia in worms are stimulated causing

tonic paralysis and expulsion of live worms.Interference with carbohydrate metabolism

(inhibition of fumarate reductase) may also be

contributing.

Single dose of 50, 100, 150 mg according to

weight.

Immunomodulator


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Diethylcarbamazine :

It acts by immobilizing the microfilaria andrender them susceptible to host defense

Well absorbed orally

Used mainly in the drug of choice forFilariasis and Visceral larva migrans


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Diethylcarbamazine : Piperazine derivative.

Diethylcarbamazine has a highly selective effect on

microfilariae (Mf).

A dose of 2 mg/kg TDS clears Mf of W. bancrofti and B.

malayi from peripheral blood in 7 days.

However, Mf present in nodules and transudates

(hydrocoele) are not killed.

Mechanism of action- alteration of Mf membranes so that

they are readily phagocytosed by tissue fixed monocytes,

but not by circulating phagocytes.

Muscular activity of the Mf and adult worms is also

affected causing hyperpolarization due to the piperazine

moiety,

active against Mf of Loa loa and onchocerca volvulus


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Filariasis: 2 mg/kg TDS produces rapid smptomatic

relief.

However, the adult worm survives in the lymphatics and

gives rise to intermittent microfilaraemia and symptoms.

Elephantiasis due to chronic lymphatic obstruction is not

affected by DEC, because fibrosis of lymphatics is

irreversible.

Yearly treatment with a combination of DEC and

albendazole on mass scale has brought downtransmission of filariasis by reducing microfilaraemia.

Tropical eosinophilia: 2 mg/kg TDS for 2-3 weeks


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Mazzoti reaction

Onchocerciasis t/t with DEC

Fever, urticaria, swollen tender LN,tachycardia, hypotension, arthralgia,

oedema.


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Ivermectin :

obtained from Streptomyces avermitilis

Ivermectin is the drug of choice for single dose

treatment of onchocerciasis and strongyloidosis,and is comparable to DEC for bancroftian and

brugian filaria. It is also highly effective in

cutaneous larva migrans and ascariasis,

while efficacy against Enterobius and Trichuris is

moderate.

Certain insects, notably scabies and head lice

are killed by ivermectin.


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It acts through a special type of glutamate gated

Cl- channel found only in invertebrates.

Such channels are not involved in the motor

control of flukes and tapeworms which are

unaffected by ivermectin. Potentiation of GABAergic transmission in the

worm has also been observed.

The lack of GABA-related actions in man could

be due to its low affinity for mammalian GABA

receptors and its exclusion from the brain,

probably by P-glycoprotein mediated efflux at

the blood brain-barrier.


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Ivermectin :

Well absorbed orally, metabolized in liver and

excreted in feces.

Contraindicated in pregnancy

does not cross mammalian blood / brain barrier

Drug can act as a GABA agonist causing

increased muscular contaction e.g Levamisol Used for Onchocerca volvulus, strongyloides

and cutaneous larva migrans.


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Ivermectin has replaced DEC for

onchocerciasis and has been used in the

'river blindness' control programme of

WHO in Africa and Latin America.

Ivermectin is the only drug effective orally

in scabies and pediculosis. Single 0.2

mg/kg dose cures most patients.


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Praziquantel :

It acts by increasing the permeability of

tegument to calciumparalysis of the

parasite.

Well absorbed orally

Good tissue distributionCNS.

Metabolites are excreted in bile and urine


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Praziquantel :

Active against trematodes like

Chinese liver flukeClonorchis sinesisLung fluke ---- Paragonimus westermani

SchistosomiasisSchistosoma sp

Also active against Cestodes


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Praziquantel :

Not advised for ocular cysticercosis

because of destruction of the organism in

the eye may damage eye.


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Bithionol used for the treatment of

fasciola hepaticasheep liver fluke.


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Niclosamide

Acts by inhibition of parasite mitochondrialphosphorylation of ADP to ATP.

The drug is lethal for Cestodes scolex andsegments but not for ova.

Laxative is used to purge all the dead

segments of the intestineova liberationand absorption can lead to cysticercosis.

It is used for most Cestodes infections.


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Niclosamideblocks glucose uptakeby intestinal tapeworms. It may

cause some mild gastrointestinal symptoms.

Piperazinemay cause hypersensitivity reactions, neurologicalsymptoms (including worm wobble) and may precipitate epilepsy.

Praziquantelparalyses both adult worms and larvae. It is extensively

metabolised. Praziquantel may cause nausea, headache, dizziness

and drowsiness; it cures with a single dose (or divided doses in oneday).

Mebendazoleblocks glucose uptakeby nematodes. Mild GI

distarbunces may be caused, and it should not be used in preg-

nancy or in children under the age of 2.

Albendazoleis similar to mebendazole.

Levamisoleparalyses the musculatureof sensitive nematodes which,

unable to maintain their anchorage, are expelled by normal peristalsis.

It is may cause abdominal pain, nausea, vomiting, headache anddizziness.


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Thiabendazole inhibits cellular enzymes of susceptiblehelminths. Gastrointestinal, neurological and hypersensitivity

reactions, liver damage and crystalluria may be induced.

Pyranteldepolarises neuromuscular junctionsof susceptible nematodes which are expelled in the faeces. It

cures with a single dose. It may induce GI disturbance,

headache, dizziness, drowsiness and insomnia.Diethylcarbamazinekills both microfilariae and adult worms.

Fever, headache, anorexia, malaise, urticaria, vomiting and

asthmatic attacks following the first dose are due to products of

destruction of the parasite, and reactions are minimised by

slow increase in dosage over the first 3 days.

Ivermectinmay cause immediate reactions due to the death

of the microfilaria. It can be effective in a single dose, but is

best repeated at 612-month intervals.


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Anthelminths

Drugs that are active against roundworms and flatworms Benzimidazoles

Macrocyclic lactones

Symptoms of a round or flatworm infection: Loss of appetite, distended abdomen, painful abdomen,

coughing, fever, vomiting, diarrhoea, listlessness and generallyfeeling unwell

Can lead to malnutrition and anemia, with a small chance ofmore severe problems due to wandering worms


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Niclosamide

Active against T. saginata, D. latum,

H. nana(6 days), D. caninum, T. solium

(risk of autoinfection due to disintegration;

prefer praziquantel).

Molluscicide used in snail control

programs (Bayluscide WP 70).

Pearson R.D. 2005. Chapter 41, In Mandell G.L. etal.


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Praziquantel

Works by:

Disrupting the membrane of the schistosome that coats the

parasite with host molecules

Causing the rapid influx of calcium ions into the parasite,

resulting in muscular tetany Paralysis of adult worms, ...

Over 80% is absorbed after an oral dose.

Adverse effects are mild but common (in over 30% of

patients): dizziness, lethargy, headache, nausea,abdominal pain, ...

Active against almost all trematodes (including all

schistosomes, but not Fasciola hepatica) and cestodes.

I ti I


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Ivermectin I Related to avermectin, also produced by

Streptomyces avermitilis. By interfering with the target animal's nervous

system. These drugs kill by interfering with the target animal's nervous

system

Drugs bind to glutamate-gated Cl ion channels in the musculature of theworm

This binding causes an unregulated ion flux through the cellsmembranes

Paralysis of the parasite

Active on most common intestinal worms(except tapeworms), most mites, and some lice.

Used for Strongyloidesstercoralis,onchocerciasis, body lice, and scabies.

Common for animal use (e.g. heartworm


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Ivermectin II

Category IV, or very low toxicity. Occasional Mazzoti-type (anaphylactoid) reactions seen

in onchocerciasis.

Available for human use in the US, Canada, France, TheNetherlands ...

Mectizan Donation Program (MDP) by Merck & Co., Inc.,in collaboration with the WHO,

Elimination of lymphatic filariasis (LF) in areas that are

co-endemic for onchocerciasis and lymphatic filariasis.Mectizan is co-administered with albendazole, which isdonated by GlaxoSmithKline, in these settings.


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schistosomiasis

Drugs that are active against schistosomiasis Currently, praziquantel is the most common drug used for the

treatment of all species of schistosomes

The drug artemisinin, an antimalarial, is also effective againstschistosomes

Symptoms of schistosomiasis: May develop a rash or itchy skin, fever, chills, cough, and

muscle aches during the early phases of infection

Most people have no symptoms at this early phase of infection

The eggs of the parasite can damage the liver, intestines, lungs,and bladder

Schistosomes are very difficult to kill because theydisguise themselves within the host by coating theirouter membrane with the hosts own molecules

The immune system will not respond to an infection, because itwill not recognize the invading schistosomes as a threat


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Worms (helminths) Drug of choice

Tapeworms (cestodes) Niclosamide or Praziquantel orAlbendazole

Roundworms (nematodes)Enterobius vermicularis(pinworm)

Ascaris lumbricoides

Trichuris trichiura(whipworm)

Trichinella spiralis (trichinellosis)

Strongyloides stercoralis

Necator americanus(hookworm)

Ancylostoma duodenale

Onchocerca volvulus(Onchocercosis)

Wuchereria bancrofti (Elephantiasis)

Mebendazole or Pyrantel


Mebendazole or Albendazole

Mebendazoleand Thiabendazole

Thiabendazole


Mebendazole, Pyrantel or

Albendazole

Ivermectin

Diethylcarbamazine

Flukes (trematodes)

Antiparasitic Drugs

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