Anthelmentics

PY-IV B.Pharm-MBA

MedChem-III
• Anthelmintics are drugs that have the capability of ridding
the body of parasitic worms or helminths.
• Helminths parasitic to humans and other animals are
derived from two phyla, Platyhelminthes (Flatworms) and
Nemathelminthes (roundworms). Cestodes (tapeworms)
and trematodes (flukes) belong to the former, and
nematodes or true roundworms belong to the latter.
• Human tapeworm and fluke infestations are rarely seen in
the United States.
• Several classes of chemicals are used as anthelmintics and
include phenols and derivatives, piperazine and related
compounds, antimalarial compounds , various heterocyclic
compounds, and natural products.
 Piperazine
• Hexahydropyrazine or diethylenediamine occurs as colorless, volatile
crystals of the hexahydrate that are freely soluble in water.
• After the discovery of the anthelmintic properties of a derivative
diethylcarbamazine, the activity of piperazine itself was established.
• Piperazine is still used as an anthelmintic for the treatment of pinworm
(Enterobius [Oxyuris] vermicularis) and roundworm (Ascaris lumbricoides)
infestations.
• It is available in various salt forms, including the citrate (official in the USP)
in syrup and tablet forms.
• Piperazine blocks the response of the ascaris muscle to acetylcholine,
causing flaccid paralysis in the worm, which is dislodged from the
intestinal wall and expelled in the feces.
 Pyrantel Pamoate
• It is a depolarizing neuromuscular blocking agent that causes spastic
paralysis in susceptible helminths. It is used in the treatment of infestations
caused by pinworms and roundworms (ascariasis).
• Because its action opposes that of piperazine, the two anthelmintics should
not be used together.
• More than half of the oral dose is excreted in the feces unchanged. Adverse
effects associated with its use are primarily gastrointestinal.
 Oxamniquine

It is an antischistosomal agent that is indicated for the treatment of Schistosoma mansoni

(intestinal schistosomiasis) infection.

Oxamniquine was originally investigated in the 1960s and was found to have limited
antiprotozoal activity, with activity against Schistosoma mansoni but no activity against the
other two schistosomal organisms.

It has been shown to inhibit DNA, RNA, and protein synthesis in schistosomes (MOA).

The oral bioavailability of oxamniquine is good; effective plasma levels are achieved in 1 to
1.5 hours.

The plasma half-life is 1 to 2.5 hours.

The drug is extensively metabolized to inactive metabolites, of which the principal one is
the 6-carboxy derivative.
Oxamniquine is activated by the organism via esterification to a biologic ester that
spontaneously dissociates to an electrophile, which alkylates the helminth DNA,
leading to irreversible inhibition of nucleic acid metabolism.

Resistant helminths do not esterify oxamniquine; therefore, activation does not

occur. Other metabolic reactions consist of oxidative reactions, leading to
inactivation. The metabolites are excreted primarily in the urine.
 Therapeutic Application

Oxamniquine is readily absorbed following oral administration and has a relatively

short half-life.

The drug has been highly effective against Schistosoma mansoni native to Brazil,

where it is marketed under the trade name Mansil.

It is also beneficial against west African S. mansoni and is supplied under the

trade name Vansil. Side effects are minimal, with transient dizziness being
reported.

The major drawback is its high cost. Encouraging outcomes have been reported
with the combination of oxamniquine and PZQ (Praziquentel).

Oxamniquine is generally well tolerated. Dizziness and drowsiness are

common, but transitory, side effects. Serious reactions, such as epileptiform
convulsions, are rare
Benzimidazole Anthelmentics
 Thiabendazole

• 2-(4-Thiazolyl)benzimidazole occurs as a white crystalline substance that is

only slightly soluble in water but is soluble in strong mineral acids.
• Thiabendazole is a basic compound with a pKa of 4.7 that forms complexes
with metal ions.
• Thiabendazole inhibits the helminth-specific enzyme fumarate reductase
(anaerobic respiration- oxidation of NADH to NAD). Inhibition of the
enzyme will uncouple oxidative phosphorylation, which is required for ATP
synthesis It is not known whether metal ions are involved or if the inhibition
of the enzyme is related to thiabendazole’s anthelmintic effect. Benzimidazole
anthelmintic drugs such as thiabendazole and mebendazole also arrest
nematode cell division in metaphase by interfering with microtubule
assembly. They exhibit a high affinity for tubulin, the precursor protein for
microtubule synthesis.
• Thiabendazole has broad-spectrum anthelmintic activity. It is used to
treat enterobiasis, strongyloidiasis (threadworm infection), ascariasis,
uncinariasis (hookworm infection), and trichuriasis (whipworm
infection). It has also been used to relieve symptoms associated with
cutaneous larva migrans (creeping eruption) and the invasive phase of
trichinosis. In addition to its use in human medicine, thiabendazole is
widely used in veterinary practice to control intestinal helminths in
livestock.
The benzimidazoles have limited water solubility and, as a result, are poorly
absorbed from the GI tract (a fatty meal will increase absorption).

Poor absorption can be beneficial, because the drugs are used primarily to treat
intestinal helminths.

To the extent that the drugs are absorbed, they undergo rapid metabolism in the
liver and are excreted in the bile
 Mebendazole
• Methyl 5-benzoyl-2-benzimidazolecarbamate (Vermox) is a broad-spectrum
anthelmintic that is effective against various nematode infestations, including
whipworm, pinworm, roundworm, and hookworm.

• Mebendazole irreversibly blocks glucose uptake in susceptible helminths,

thereby depleting glycogen stored in the parasite. It apparently does not
affect glucose metabolism in the host. It also inhibits cell division in
nematodes.

• Mebendazole is poorly absorbed by the oral route.

• Adverse reactions are uncommon and usually consist of abdominal

discomfort. It is teratogenic in laboratory animals and, therefore, should not
be given during pregnancy.
 Albendazole

• Methyl 5-(propylthio)-2-benzimidazolecarbamate is a broad-spectrum

anthelmintic that is not currently marketed in North America. Albendazole is
widely used throughout the world for the treatment of intestinal nematode
infection.
• It is effective as a single-dose treatment for ascariasis, New and Old World
hookworm infections, and trichuriasis. Multiple-dose therapy with albendazole can
eradicate pinworm, threadworm, capillariasis, clonorchiasis, and hydatid disease.
• Albendazole occurs as a white crystalline powder that is virtually
insoluble in water. The oral absorption of albendazole is enhanced by a
fatty meal.

• The drug undergoes rapid and extensive first-pass metabolism to the

sulfoxide, which is the active form in plasma.

• The elimination half-life of the sulfoxide ranges from 10 to 15 hours.

Considerable biliary excretion and enterohepatic recycling of albendazole
sulfoxide occurs.

• Albendazole is generally well tolerated in single-dose therapy for

intestinal nematodes. The highdose, prolonged therapy required for
clonorchiasis or echinococcal disease therapy can result in adverse effects
such as bone marrow depression, elevation of hepatic enzymes, and
alopecia.
Albendazole is unique in two ways. First, the presence of a thioether substituent
at the five position increases the likelihood of sulfur oxidation. Second, the initial
metabolite, albendazole sulfoxide, is a potent anthelmintic. This initial oxidation
is catalyzed principally (70%) by CYP3A4 and CYP1A2 and (30%) by flavin-
containing monooxygenase, giving rise to a compound that is bound to plasma
protein. This intermediate has an expanded utility in that it has been shown to be
active against the hydatid cyst found in echinococciasis, a tapeworm disease.
Further oxidation by cytochrome P450 leads to the inactive sulfone. Additional
metabolites of the sulfone have been reported that include carbamate hydrolysis to
the amine and oxidation of the 5-propyl side chain. These reactions occur only to a
minor extent.

inactive sulfone
 Praziquantel
• It is a broadspectrum agent that is effective against various trematodes (flukes). It
has become the agent of choice for the treatment of infections caused by
schistosomes (blood flukes). The drug also provides effective treatment for
fasciolopsiasis (intestinal fluke), clonorchiasis (Chinese liver fluke), fascioliasis
(sheep liver fluke), opisthorchosis (liver fluke), and paragonimiasis (lung fluke).
• Praziquantel increases cell membrane permeability of susceptible worms,
resulting in the loss of extracellular calcium. Massive contractions and
ultimate paralysis of the fluke musculature occurs, followed by phagocytosis
of the parasite.
• Following oral administration, about 80% of the dose is absorbed. Maximal
plasma concentrations are achieved in 1 to 3 hours. The drug is rapidly
metabolized in the liver in the first-pass. It is likely that some of the metabolites
are also active. Praziquantel occurs as a white crystalline solid that is insoluble in
water. The drug is generally well tolerated.
More than one mechanism of action can exist for PZQ, possibly depending on the
type of parasite being treated. The mechanism of action appears to involve
Ca2+ redistribution either directly or indirectly. In the case of helminths found
in the lumen of the host (cestode infection), the drug leads to muscle
contraction and paralysis, leading in turn to worm expulsion.

Additionally, PZQ has been shown to inhibit phosphoinositide metabolism,

which by an undetermined mechanism leads to the worm paralysis. With
intravascular-dwelling schistosomes (parasitic flatworms), PZQ leads to drug-
induced damage of the tegument of the worm. As a result, antigens in the
helminth are subject to attack by immune antibodies of the host. An antigen–
antibody immunologic reaction leads to the death of the parasite. Finally, PZQ
affects glycogen content and energy metabolism
PZQ is rapidly absorbed and undergoes hepatic first-pass metabolism. The
metabolites are either less active or inactive and consist of hydroxylated
compounds. In the serum, the major metabolite appears to be the
monohydroxylated 4-hydroxycyclohexylcarboxylate, whereas in the urine, 50% to
60% of the initial PZQ exists as dihydroxylated products. These hydroxylation
reactions are catalyzed by CYP2B6 and CYP3A4. The metabolites would be
expected to exist in the conjugated form in the urine.