Anthelmintics

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Anthelmintics
Dr\ Moustafa K Soltan
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:
.2) Blood flukes:
3) Intestinal flukes:
Fasciola Hepatica.
Fasciola Gigantica
Schistosoma haematobium.
Heterophyes heterophyes.
Class: Cestodes ( Tapeworms )
Beef tapeworm:Taenia saginata.
Pork tapeworm:Taenia solium.
Dwarf tapeworm:Hymenolepis nana.
Schistosoma mansoni.
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
N
N
H
H
H2C
COO
HO C
COO
H2C
COO
2
Piperazine citrate.
3
Hexahydropyrazine citrate
diethylenediamine citrate
Synthesis of piperazine citrate:
NH3
Cl
+
Cl
Diethylcarbamazine citrate.
ET
ET
Cl
N
C
O
H2C
HO C
H2C
1
N
4 H
2 3
COOH
COO
H
N
ET
O
N C
Cl
ET
ET
N
N
H
N,N-diethylcarbamoyl
prepared
chloride.
as above
-HCl
COOH
1-Diethylcarbamoyl-4-methyl
piperazine dihydrogen citrate
drug.
N
H
CH3
N
citric acid
+
NH3
Cl
H
N
drug
citric acid
ET
NH
C
O
HCHO / HCOOH
N-methylation
ET
N
ET
N
N
C
O
N CH3
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
1) drug of choice in treatment of filariasis.2) active against ascariasis.
( note that piperazine citrate and diethyl carbamazine citrate are vermifuges and
note the mechanism, while diethylcarbamazine citrate is vermicide for filarial ).
III] Benzimidazole derivatives:
Mebendazole
Thiabendazole
1S
2
2
O
H1
N
H3CO
N 4
N
3
3
2-(thiazol-4-yl)1H-benzimidazole
H3CO
Flubendazole
O
H1
2N
N
H
N
H
N
H 2N
5
3 4
methyl-N-(5-benzoyl-1Hbenzimidazol-2-yl) carbamate
Albendazole
H1
H 2N
N
O
F
4 5
3
methyl-N-(5-(4-fluorobenzoyl)-1Hbenzimidazol-2-yl) carbamate
O
1N
H3CO
N
3 45 S
methyl-N-(5-propylthio-1Hbenzimidazol-2-yl) carbamate
O
CH3
Synthesis of thiabendazole
S
Cl
Cl
+
N
CN H2N
Cl
Cl
AlCl3
S
N
-
N+H3 Cl
N
H
Na2CO3
-HCl
thiabendazole
SAR of benzimidazole derivatives
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 don 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.
pyrantel pamoate = pyrantel embonate
4
5
6
COOH
N3
N 2
1
CH3
OH
2 S
1
CH2
OH
COOH
trans-1,4,5,6-tetrahydro-1-methyl-2[2-(2-thienyl)vinyl]pyrimidine pamoate
( vinyl = ethenyl )
Synthesis
N
N
N
O
CH3 +
H
S
basic or
N
acidic media
thiophene-2aldehyde.
active methylene
make condensation
drug
with carbinyl group.
CH3
CH3
S
Pamoic acid
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
H3C
5
N6
4
1
3
2
2
COO
4 3 OH
CH2
OH
N 2
3 4
CH3 1 2
5
N
H3C
1 CH3
COO
2
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 S
a
b
N
7N
1
S1
2
N
HCl
6
3
5 4
(s)-2,3,5,6-tetrahydro-6-phenylimidazolo
[2,1-b]thiazole HCl (or)
nomenclate the drug as bicyclo form....
assay: non aqoueous titration as weak base
S isomer or Levo isomer is the active form.
H
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
OH
3
2 1
Cl
O
1
N
H
4
5
2
3
4
NO2
Cl 5-Chloro-N-(2-chloro-
4-nitrophenyl)-2-hydroxybenzamide
( 2-hydroxybenzamide = salicylamide )
2-,5-dichloro-4--nitro salicylanilide
Synthesis of niclosamide.
OH
OH
O
Cl
COOH
H2N
Cl
SOCl2
+
Cl
2-hydroxy-5-chloro
benzoic acid
Cl
NO2
-HCl
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)
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