Anthelmintics
•
Anthelmintics
are drugs that have the capability of ridding the body of parasitic worms or
helminths
•
Helminths
that infect human hosts are divided into two categories, or phyla:
•
a)
Platyhelminthes (flatworms)- include the classes Cestode (tapeworms) and
Trematode (flukes or schistosomes)
•
b)
Aschelminthes or nematodes (roundworms)- roundworm, hookworm, pinworm, and
whipworm. These worms are cylindrical in shape, with significant variations in
size, proportion, and structure
•
Nematode Infections
•
Ancylostomiasis or Hookworm Infection- American hookworm (Necator americanus)
and the “Old World” hookworm (Ancylostoma doudenale).
•
Enterobiasis or Pinworm Infection- Enterobius vermicularis
•
Ascariasis or Roundworm Infections- Ascaris lumbricoides
•
Trichuriasis or Whipworm Infections- Trichuris trichiura
•
Trichinosis or Trichina Infection- Trichinella spiralis
•
Filariasis- Wuchereria bancrofti, Brugia malayi, and Brugia timori
•
Cestode and Trematode Infections
•
Cysticercosis or Tapeworm Infection
•
Beef
tapeworm (Taenia saginata)
•
Pork
tapeworm (Taenia solium)
•
Dwarf
tapeworm (Hymenolepis nana)
•
Fish
tapeworm (Diphyllobothrium latum)
•
Schistosomiasis or Blood Flukes- Schistosoma hematobium, Schistosoma mansoni, and Schistosoma japonicum
Diethylcarbamazine citrate
•
Highly
water-soluble crystalline compound that has selective anthelmintic activity
•
It is
effective against various forms of filariasis, including Bancroft,
onchocerciasis, and laviasis
•
It is also active against ascariasis
•
Mechanim-
not clearly known
•
Suggestion-
inhibition of microtubule polymerization and disruption of preformed
microtubules
•
Or
interference with arachidonic acid metabolism
•
Adverse
reactions- anaphylactic reactions, intense pruritus, and ocular complications
Thiabendazole
•
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
•
Mechanism-
inhibits the helminth-specific enzyme fumarate reductase (important enzyme in
helminthes that appears to be involved in oxidation of NADH to NAD for ATP
production)
•
Also arrest nematode cell division in
metaphase by interfering with microtubule assembly and exhibit a high affinity
for tubulin, the precursor protein for microtubule synthesis
•
Has
broad-spectrum anthelmintic activity
•
It is
used to treat enterobiasis, strongyloidiasis (threadworm infection),
ascariasis, uncinariasis (hookworm infection), and trichuriasis (whipworm
infection)
•
Also used
to relieve symptoms associated with cutaneous larva migrans (creeping eruption)
and the invasive phase of trichinosis.
•
Widely
used in veterinary practice to control intestinal helminths in livestock
Mebendazole
•
Broad-spectrum
anthelmintic that is effective against various nematode infestations, including
whipworm, pinworm, roundworm, and hookworm
•
Mechanism-
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
•
Poorly absorbed by the oral route
•
Adverse
reactions are uncommon and usually abdominal discomfort
•
It is
teratogenic in laboratory animals and should not be given during pregnancy
Albendazole
• Broad-spectrum
anthelmintic that is not currently marketed in North America
• 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
• Effectiveness
of albendazole against tapeworms (cestodes) is generally more variable and less
impressive
• White
crystalline powder that is virtually insoluble in water
• Oral
absorption of albendazole is enhanced by a fatty meal
• Drug
undergoes rapid and extensive first-pass metabolism to the sulfoxide, which is
the active form in plasma
• Elimination
half-life of the sulfoxide ranges from 10 to 15 hours
• High
dose can result in adverse effects such as bone marrow depression, elevation of
hepatic enzymes, and alopecia
Niclosamide
• Occurs
as a yellowish white, water-insoluble powder
• Potent
taeniacide that causes rapid disintegration of worm segments and the scolex
• Penetration
of the drug into various cestodes appears to be facilitated by the digestive
juices of the host
• Niclosamide
is well tolerated following oral administration, and little or no systemic
absorption of it occurs
• A
saline purge 1 to 2 hours after ingestion of the taeniacide is recommended to
remove the damaged scolex and worm segments- mandatory
Oxamniquine
• Antischistosomal
agent that is indicated for the treatment of Schistosoma mansoni (intestinal
schistosomiasis) infection
• Mechanism-
Shown to inhibit DNA, RNA, and protein synthesis in schistosomes
• 6-hydroxymethyl
group is critical for activity;
• metabolic
activation of precursor 6-methyl derivatives is critical
• Free
base occurs as a yellow crystalline solid that is slightly soluble in water but
soluble in dilute aqueous mineral acids and soluble in most organic solvents
• Dizziness
and drowsiness are common, but transitory, side effects
• Serious
reactions, such as epileptiform convulsions, are rare
Praziquantel
• Broad-spectrum
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)
• Effective treatment
for fasciolopsiasis (intestinal fluke), clonorchiasis (Chinese liver fluke),
fascioliasis (sheep liver fluke), opisthorchosis (liver fluke), and
paragonimiasis (lung fluke)
• Mechanism-
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
• Oral
administration, about 80% of the dose is absorbed
• Drug
is rapidly metabolized in the liver in the first-pass
• White
crystalline solid that is insoluble in water
Ivermectin
• Is
a mixture of 22,23-dihydro derivatives of avermectins B1a and B1b
prepared by catalytic hydrogenation
• Avermectins
are members of a family of structurally complex antibiotics produced by
fermentation with a strain of Streptomyces avermitilis
• Ivermectin
is active in low dosage against a wide variety of nematodes and arthropods that
parasitize animals
• Structure-
pentacyclic 16-membered–ring aglycones glycosidically linked at the 3-position
to a disaccharide that comprises two oleandrose sugar residues
• Side
chain at the 25-position of the aglycone is sec-butyl in avermectin B1a,
whereas in avermectin B1b, it is isopropyl
avermectins B1a
(-C2H5) and B1b (-CH3)
• Ivermectin
contains at least 80% of 22,23-dihydroavermectin B1a and no more
than 20% 22,23-dihydroavermectin B1b
• Widespread
use in veterinary practice in the United States and many countries throughout
the world for the control of endoparasites and ectoparasites in domestic
animals
• It
has been found effective for the treatment of onchocerciasis (“river
blindness”) in humans, an important disease caused by the roundworm Oncocerca
volvulus
• Mechanism-
It blocks interneuron–motor neuron transmission in nematodes by stimulating the
release of the inhibitory neurotransmitter GABA
Diethylcarbamazine citrate- Synthesis
Mebendazole- Synthesis
