Anthelmintics

Dr.Amal Belaid
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• The term anthelmintic is restricted to drugs acting locally to
expel parasites from gastro intestinal tract. There are several
types of worms which penetrate other tissues, drugs which
act on these parasitic infections are also known as
anthelmintics.
• The worm parasites of man belong to two phyla:
Nemathelminthes (round- worms) and platyhelminthes
(flatworms). The roundworms include hookworm,
whipworm, pinworm Strongyloides stercoralis, Trichinella
spiralis and Wuchereria bancrofti.
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 Helminths
 Helminths (from the Greek Helmins, meaning
worm).
 Parasitic worms or helminths are a division
of eukaryotic parasites that, unlike external
parasites such as lice and fleas, live inside their
host.
 They are worm-like organisms that live and
feed off living hosts, receiving nourishment and
protection while disrupting their hosts' nutrient
absorption, causing weakness and disease.
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 It has been estimated that about Half of
country’s population suffers from
helminthiasis, and number is on increase.
 It is not only limited to tropical & subtropical
countries, but is also endemic in many
regions because of poor sanitation, poor
family hygiene, malnutrition, and crowded
living condition.
 They are also causes blood loss, nutritional
deficiencies, urticaria, allergic manifestation
and even intestinal obstruction.
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There are 3 classes of Helminths:
 Nematodes(roundworms)
Ascaris lumbricoides (roundworm),
Enterobius vermicularis (threadworm),
Trichuris trichiura (whipworm),
Necator americanus and
Ankylostoma duodenale (hookworms).
 Trematodes (flukes)
Schistosoma haematobium,
Schistosoma mansoni, and
Schistosoma japonicum.
 Cestodes (tapeworms)
Taenia saginata, Taenia solium,
Hymenolepis nana and
Diphyllobothrium
5 latum..
 Intestinal Worms
A) Round worms
(Nematodes)
Ascaris lmubricods (common, Round
worm )
 Enterobius vermicularis (pin worm)
 Trichris trichuria (whip worm)
 Strongyloids stercoralis (thread
worm)

6 Ankylostoma dudenale (hook worm)
 B) Tape worms (cestodes)
• Taenia saginata ( Beef)
• Taenia solium ( pork)
• Fish tapeworm – Diphyllobothrium latum

Humans become infected by eating raw or unde

cooked meat containing larvae of infected cattle or pig.

In some cases the larva gets encysted in muscles ,

viscera , brain , eye resulting in cysticercosis

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 Tissue worms
• Filariae ( bancrofti, loa loa )
Adult filariae live in the lymphatics , causing
lymphadenitis , swelling of limb. Microfilariae
goes to blood stream to be ingested by
mosquitoes

• Trichnella spiralis : larva migrats from

intestine to tissues of leg or foot producing
ulcer
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Anthelmintics. (Anti = against, helminthes = worms)
Vermicides : Drugs that kill worms
Vermifuges :Drugs that expel the worms from the body by

1)Peristaltic movement of intestine, or

2)cathartic and purgative action.

Characters of ideal anthelmintics:

1) Orally active.
2) Effective in single dose.
3) Inexpensive.
4) Wide safety margin between toxicity to worm and toxicity
to host
 Classification of Helminthes: they are two phyla **

Phylum: Nemathelminthes. Class: Nematodes (true round worms)

 I) Intestinal Nematodes: 1) Round worms as Ascaris. 2) Hookworms as
Ancylostoma. 3) Pinworms as Oxyuris. 4) Whipworms as Trichuris.
5) Thread worms as Strongyloids. 6) Enterobius Vermicularis.
II) Tissue Nematodes:Filaria.
Phylum: Platyhelminthes ( flatworms)
Class: Termatodes ( Flukes ) 
1) Liver flukes: Fasciola Hepatica. Fasciola Gigantica
.2) Blood flukes: Schistosoma haematobium. Schistosoma mansoni.
3) Intestinal flukes: Heterophyes heterophyes.
Class: Cestodes ( Tapeworms ) 
Beef tapeworm:Taenia saginata.
Pork tapeworm:Taenia solium.
Dwarf tapeworm:Hymenolepis nana.
 A] Drugs active on Nematodes:

I] Chlorinated compounds: CCl4 , tetrachloroethylene.

II] Piperazine derivatives: piperazine citrate,

diethylcarbamazine citrate.

III] Benzimidazole derivatives: Thiabendazole, Mebendazole,

Flubendazole, and Albendazole.

IV] Vinylpyrimidine derivatives: Pyrantel pamoate.

V] Dyes:( cyanine dyes ): Pyrivinium pamoate

VI] Imidazothiazoles: Levimasole.

I] Chlorinated compounds: CCl4 , tetrachloroethylene.
CCl4
Must be followed by purgative to remove dead worms and excess drug.
**Its side effects are 1)liver necrosis.
2) not used during pregnancy, otherwise make liver and kidney damage to the
fetus
tetrachloroethylene.
MOA: Cause irritation to the worm tissue. Used in Treatment of roundworm
infestations. Less toxic than CCl4, but all halogenated hydrocarbons cause liver
and kidney degeneration
II] Piperazine derivatives: piperazine citrate, diethylcarbamazine citrate

H H H2C COO
N
HO C COO
H2C COO
N
H H 2
Piperazine citrate.
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Hexahydropyrazine citrate
diethylenediamine citrate
 Synthesis of piperazine citrate:

H
Cl NH3 Cl N
citric acid
+ + drug.
Cl NH3 Cl N
H

H ET O
Diethylcarbamazine citrate. N
N C Cl ET
ET CH3 ET
N N N N N N NH
ET C 1 4 H H N,N-diethylcarbamoyl ET C
O 2 3 prepared chloride. O
as above -HCl HCHO / HCOOH
H2C COOH
N-methylation
HO C COO ET
citric acid
H2C COOH drug N N N CH3
ET C
1-Diethylcarbamoyl-4-methyl O
piperazine dihydrogen citrate
Piperazine citrate.Block the response of Ascaris muscle to acetylcholine at
neuromuscular junction causing flaccid paralysis in worms which become
easily dislodged by gut movement, expelled in faeces
Treatment of roundworms as ( Ascaris ),Or pinworms like ( Enterobius .
.vermicularis or Oxyuris) infestations

DiethylCarbamazineCitrate.1) same to that of piperazine citrate due to

piperazine moiety.2) diethylcarbamazine cause alterations in the microfilarial
surface membranes, thereby rendering them recognized as foreign bodies by the
host and destroyed by its defense mechanism

.drug of choice in treatment of filariasis.2) active against ascariasis )1

note that piperazine citrate and diethyl carbamazine citrate are vermifuges and (
.) note the mechanism, while diethylcarbamazine citrate is vermicide for filarial
III] Benzimidazole derivatives:
Thiabendazole Mebendazole
O H
1S H1 1N O
N N
2 2 H3CO
2NH
N 4 N 5
3 3 4
3 methyl-N-(5-benzoyl-1H-
2-(thiazol-4-yl)1H-benzimidazole benzimidazol-2-yl) carbamate

Flubendazole
O Albendazole
H1 O
N H1
N
2 H 2N
H3CO F H3CO N
H N CH3
3 4 5 3
N 5 S
O 4
methyl-N-(5-(4-fluorobenzoyl)-1H-
methyl-N-(5-propylthio-1H-
benzimidazol-2-yl) carbamate
benzimidazol-2-yl) carbamate
 Synthesis of thiabendazole
1,1,2,2-Te trac hloro-e thene
S Cl Cl N +H 3 C l-
S
+ Cl
Cl
N CN H 2N N
Phe nylam ine A lC l 3 N
Thia zol-4-ylm ethylidyne -am m onium H
N a2C O 3
-H C l
thia benda zole

C -Phe nylam ino-C -thia zol-4-yl-m ethyl-am m onium ; chloride

12 7
1S 11 H 6
SAR of benzimidazole derivatives N 1 5
13 8
N 140
N 2 4
14
9 3
1) 5-substituents do not necessary increase potency, `But when R in C5 is group
prevent metabolic inactivation such as hydroxyl group, the resulting compound has
greater anthelmintic activity.
2) 2-substituents may be methyl carbamate
(--NHCOCH3 ) or an aromatic ring without loss of
anthelmintic potency, but those with aromatic or heterocyclic ring are more toxic
than those with carbamate. ( thiabendazole is the most toxic one).
Mode of action:
1) inhibition of certain enzyme: which is fumarate reductase system of
the worm thereby interfering with an important energy source.
2)-inhibition of the cell division: inhibit nematode cell division in the
metaphase by interfering with the microtubule assembly

3)-They have high affinity for tubulin, the precursor protein, necessary for
microtubule synthesis.

4)-they make irreversible blockade of glucose uptake by susceptible

helminthes, so depletion of glycogen stored within the parasite leads to
decrease in ATP, which is responsible for survival and reproduction in
helminthes.
No need for purgative use after oral administration
**all of them have broad spectrum anthelmintic activity mainly against
intestinal nematodes, but,
1) thiabendazole also used in treatment of
cutaneous larva migrans.
2)mebendazole , flubendazole and albendazole effective in some cestode
worms.
** side effects of mebendazole and albendazole:
GIT side effects in normal doses.
Liver impairment, bone marrow depression in high doses.
Should not given in pregnancy as teratogenic can cross the placenta
3) Thiabendazole in which benzimidazole ring is replaced by other rings like
imidazopyridine are usually less active than the parent drug.
4) mebendazole, flubendazole, albendazole are less toxic than thiabendazole due
to:
a- they do not have heterocyclic ring in
2 position.
b- they are less absorbed from the GIT
after oral administration than in case
of thiabendazole that is readily
absorbed from the GIT.
Vinylpyrimidine derivatives: Pyrantel pamoate.
p y ra n te l p a m o a te = p y ra n te l e m b o n a te
4 COOH
5 N3
OH
6 N 2 CH 2
1 2 S OH
CH 3
1
COOH
tra n s -1 ,4 ,5 ,6 -te tra h y d r o -1 -m e th y l-2 -
[2 -(2 -th ie n y l) v in y l]p yr im id in e p a m o a te
( v in y l = e th e n yl )
 Synthesis

N O N

N + S b a s ic o r N
CH 3 a c id ic m e d ia
H S
CH 3 th io p h e n e -2 - CH 3
a ld e h y d e .
a c tiv e m e th yle n e P a m o ic a c id
m a k e c o n d e n sa tio n
w ith c a rb in yl g ro u p . d ru g

Pyrantel Pamoate.
Depolarizing neuromuscular blocking agent that produce spastic paralysis in
susceptible helminthes followed by their expulsion from host. ( as pyrivinium
pamoate and piperazine derivatives ).*
* used in most intestinal nematode infection like pinworms and roundworms
(except whipworms).** piperazine may antagonize the effect of pyrantel so
they must not be used together.
Dyes:( cyanine dyes ).
pyrivinium pamoate = pyrivinium embonate
H3C
6 5 4 1 2
N COO
H3C
3
2
N 2 4 3 OH
3 4 CH2
CH3 1 2 5 OH
N
H3C 1 CH3 COO

6-(dimethylamino)-2-[2-(2,5-dimethyl-1-phenylpyrrol-3-yl)vinyl]-1-methyl
quinolinium salt with 4,4- -methylene bis [3-hydroxy-2-naphthoate].

PyriviniumPamoate.Exert anticholinergic effect on the worms causing paralysis

and expulsion by peristalsis ( vermifuges by the same mechanism of piperazine
derivatives that is depolarizing neuromuscular blockers)**
used for chemotherapy of pinworms.**Side effects: nausea, epigastric pain due to
local irritant effect.** drug is red cyanine dye, so leads to reddish brown stool
Imidazothiazoles. levamisole hydrochloride
3
N 2 aS
b
N
1
7N S1
2
N HCl
H 6 4 3
5
(s)-2,3,5,6-tetrahydro-6-phenylimidazolo
[2,1-b]thiazole HCl (or)
nomenclate the drug as bicyclo form....

Levamisole.1) act as Depolarizing neuromuscular blocking agent and as above in

pyrantel pamoate.2) potent stereospecific inhibitor of fumarate reductase in
various nematodes, such inhibition causes contraction in helminthes, followed
by tonic paralysis, subsequent elimination of the worm.
** used for treatment of round worm as Ascariasis, and hook worm as
ancylostomiasis.** completely absorbed from the GIT, the levo isomer is the
only active one.
Drug active on cestodes Niclosamide
Cl
OH O
2 1 2
3 N
1 3
H
4 4
5 NO2
Cl 5-Chloro-N-(2-chloro-
4-nitrophenyl)-2-hydroxybenzamide
( 2-hydroxybenzamide = salicylamide )
2-,5-dichloro-4--nitro salicylanilide
Synthesis of niclosamide.
5-Chloro-2-hydroxy-benzoyl chloride
OH OH O
COOH Cl
Cl H2N
SOCl2
+
Cl Cl NO2
2-Chloro-4-nitro-phenylamine
2-hydroxy-5-chloro -HCl
benzoic acid
drug
Niclosamide.1) interfere with helminthes metabolism where it inhibits
mitochondrial oxidative phosphorylation, inhibit respiration, block glucose
uptake by the cestode.2)after initial attack of the drug,helminthes ( taenia
solium ) become highly sensitive to the proteolytic enzymes of the host
intestine, undergo partial digestion.
** the drug of choice in treatment of most tapeworm infestations. (cestodes)
such as Taenia saginata, Taenia solium, Hymenolepis nana.
** the drug of choice in treatment of most tapeworm infestations.
(cestodes)** no systemic absorption of the drug occurs
.** the digestive juice of the host facilitates the drug penetration into various
cestodes.
** very important note:in case of Taenia solium, ( pork tapeworm):laxative
should be given within 1-2 hours after drug use to expel the dead worms and
to avoid cysticercosis [ as the drug is not active against the larval form
(cystcerci)].This cysticerci results from release of live ova from worm
segments damaged by the drug and migrate to the stomach.( now
praziquantil is the drug of choice in case of Taenia solium to avoid such
limitation)