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Antiparasitic drugs

Male fern (Dryopteris filix-mas (L.) Schott)


Anthelminthic Drugs
Vermicide- kill
Vermifuge- expell
Unlike protozoa, helminths are large and have complex
cellular structures


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
Anthelminthic drugs
Three major groups of helminths (worms)
are
Nematodes
Trematodes
Cestodes

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 fluke Clonorchis sinesis
Lung fluke ---- Paragonimus westermani
Schistosomiasis Schistosoma sp
Cestodes Tape worm
Beef tape worm Taenia saginata
Pork tape worm Taenia solium
Fish tape worm Diphyllobothrium latum
Dog tape worm Echinococcus granulosis

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 person
through an insect vector
Trypanosomes
Plasmodia


Sexual transmission
Trichomonas vaginalis
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)
Anthelminthic drugs
Drugs for helminths
Nematodes : Albendazole, Mebendazole,
Pyrantel pamoate, Diethylcarbamazine,
Ivermectin
Trematodes : Praziquantel, metrifonate,
bithionol, emetine, dehydroemetine
Cestodes : Niclosamide, Praziquantel,
Albendazole
Anti-helminthic drugs
Benzimidazole :
Thiabendazole, Albendazole & Mebendazole
Effective against wide spectrum of
nematodes
It acts by binding and interfering the
assembly of microtubules
It also decreases the glucose uptake
Inhibits the polymerization of tubulin into microtubules
This inhibition prevents cellular division and the absorption of
glucose in its intestines
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.
Has Antiinflammatory, 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.
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 and
operation 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 after
meals. Tablets must be chewed;
Uses
Because of frequent side effects and poor patient
acceptability, thiabendazole is used only when other
better tolerated drugs are ineffective.
Strongyloidosis
Cutaneous larva migrans
Mebendazole
congener of thiabendazole
it retained the broad-spectrum anthelmintic activity but not
the 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 expels Trichinella spiralis from intestines, but efficacy in
killing 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
Mechanism of action
It acts probably by blocking glucose uptake in the
parasite and depletion of its glycogen stores.
The site of action of mebendazole appears to be
the microtubular protein beta-tubulin' of the
parasite.
It binds to beta-tubulin of susceptible worms with
high affinity and inhibits its polymerization.
Intracellular microtubules in the cells of the worm
are gradually lost.
The immobilizing and lethal action of mebendazole
on worms is rather slow: takes 2-3 days to develop.
p/k- Absorption of mebendazole from
intestines is minimal; 75-90% of an oral dose
is passed in the faeces. The fraction absorbed
is 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 hair
and granulocytopenia
Pregnancy- C/I

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.
Enterobius 100 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.
Albendazole
congener of mebendazole: retains the broad-spectrum
activity and excellent tolerability of its predecessor, and has
the 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 trichuriasis have 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
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.
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 is
taken 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
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.
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. 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.
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

Benzimidazole :
Albendazole and Mebendazole are poorly
absorbed from GIT whereas thiabendazole
is well absorbed.
Albendazole and Mebendazole are well
tolerated , thiabendazole causes
hallucinations
Mebendazole and Albendazole are used
to treat intestinal nematode infections
Thiabendazole is preferred drug of choice
in cutaneous larva migrans.
Contraindicated in pregnancy
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
Used to treat round worm, hook worm and pin
worm. Efficacy comparable to mebendazole.
Lower cure rates (about 60%) have been
obtained in case of Necator infestation. It is less
active against Strongyloides and inactive against
Trichuris and other worms.
g.i. symptoms,headache and dizziness is
reported. It is tasteless, nonirritant; abnormal
migration of worms is not provoked.
Its safety in pregnant women and in children
below 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.
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.
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.
Levamisole, Tetramisole
use is restricted to ascariasis and
ancylostomiasis, 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
Diethylcarbamazine :
It acts by immobilizing the microfilaria and
render them susceptible to host defense
Well absorbed orally
Used mainly in the drug of choice for
Filariasis and Visceral larva migrans
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
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 down
transmission of filariasis by reducing microfilaraemia.
Tropical eosinophilia: 2 mg/kg TDS for 2-3 weeks
Mazzoti reaction
Onchocerciasis t/t with DEC
Fever, urticaria, swollen tender LN,
tachycardia, hypotension, arthralgia,
oedema.
Anti-helminthic drugs
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.
Acts by acting on parasites GABA chloride
channel receptors chloride influx in enhanced
hyperpolarisation and paralysis of the worm.
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.
Anti-helminthic drugs
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.

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.
Anti-helminthic drugs
Praziquantel :
It acts by increasing the permeability of
tegument to calcium paralysis of the
parasite.
Well absorbed orally
Good tissue distribution CNS.
Metabolites are excreted in bile and urine
Anti-helminthic drugs
Praziquantel :
Active against trematodes like
Chinese liver fluke Clonorchis sinesis
Lung fluke ---- Paragonimus westermani
Schistosomiasis Schistosoma sp
Also active against Cestodes
Anti-helminthic drugs
Praziquantel :
Not advised for ocular cysticercosis
because of destruction of the organism in
the eye may damage eye.
Anti-helminthic drugs
Bithionol used for the treatment of
fasciola hepatica sheep liver fluke.

Anti-helminthic drugs
Niclosamide
Acts by inhibition of parasite mitochondrial
phosphorylation of ADP to ATP.
The drug is lethal for Cestodes scolex and
segments but not for ova.
Laxative is used to purge all the dead
segments of the intestine ova liberation
and absorption can lead to cysticercosis.
It is used for most Cestodes infections.

Niclosamide blocks glucose uptake by intestinal tapeworms. It may
cause some mild gastrointestinal symptoms.

Piperazine may cause hypersensitivity reactions, neurological
symptoms (including worm wobble) and may precipitate epilepsy.

Praziquantel paralyses 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 one
day).
Mebendazole blocks glucose uptake by nematodes. Mild GI
distarbunces may be caused, and it should not be used in preg-
nancy or in children under the age of 2.
Albendazole is similar to mebendazole.

Levamisole paralyses the musculature of sensitive nematodes which,
unable to maintain their anchorage, are expelled by normal peristalsis.
It is may cause abdominal pain, nausea, vomiting, headache and
dizziness.

Thiabendazole inhibits cellular enzymes of susceptible
helminths. Gastrointestinal, neurological and hypersensitivity
reactions, liver damage and crystalluria may be induced.

Pyrantel depolarises neuromuscular junctions
of susceptible nematodes which are expelled in the faeces. It
cures with a single dose. It may induce GI disturbance,
headache, dizziness, drowsiness and insomnia.
Diethylcarbamazine kills 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.

Ivermectin may 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.

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 generally
feeling unwell
Can lead to malnutrition and anemia, with a small chance of
more severe problems due to wandering worms

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. et al.
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.


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 the
worm
This binding causes an unregulated ion flux through the cells
membranes
Paralysis of the parasite
Active on most common intestinal worms
(except tapeworms), most mites, and some lice.
Used for Strongyloides stercoralis,
onchocerciasis, body lice, and scabies.
Common for animal use (e.g. heartworm
prophylaxis).
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, The
Netherlands ...

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 is
donated by GlaxoSmithKline, in these settings.


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 against
schistosomes
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 they
disguise themselves within the host by coating their
outer membrane with the hosts own molecules
The immune system will not respond to an infection, because it
will not recognize the invading schistosomes as a threat

Worms (helminths) Drug of choice
Tapeworms (cestodes)
Niclosamide or Praziquantel or
Albendazole
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 Pyrantel
Mebendazole or Albendazole
Mebendazole
and Thiabendazole
Thiabendazole
Mebendazole or Pyrantel
Mebendazole, Pyrantel or
Albendazole
Ivermectin
Diethylcarbamazine
Flukes (trematodes)
Schistzoma (Schistozomes)

Praziquantel