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Anti-protozoal drugs
Life cycle of Entamoeba histolytica
Entamoeba histolytica exists in two forms: cysts that can survive
outside the body, and labile but invasive trophozoites that do not
persist outside the body. Cysts, ingested through fecescontaminated food or water, pass into the lumen of the intestine,
where the trophozoites are liberated. The trophozoites multiply,
and they either invade and ulcerate the mucosa of the large
intestine or simply feed on intestinal bacteria.
Note: One strategy for treating luminal amebiasis is to add
antibiotics, such as tetracycline, to the treatment regimen, resulting
in a reduction in intestinal flora the ameba's major food source.
The trophozoites within the intestine are slowly carried toward the
rectum, where they return to the cyst form and are excreted in
feces.
Large numbers of trophozoites within the colon wall can also lead
to systemic invasion.
Classification of amebicidal drug according to the site where
the drug is effective , Therapeutic agents are classified as:
1- Luminal: act on the parasite in the lumen of the bowel.
2-systemic:
and liver:
are effective against amebas in the intestinal wall
3-mixed (luminal and systemic): effective against both the
luminal and systemic forms of the disease, although luminal
concentrations are too low for single-drug treatment.
Mixed amebicides (metronidazole and tinidazole)
1-Metronidazole:
Therapeutic indications:
1- Is the mixed amebicide of choice for treating amebic infections;
it kills the E. histolytica trophozoites.
2- Metronidazole also finds extensive use in the treatment of
infections caused by :
a- Giardia lamblia.
b-Trichomonas vaginalis.
c-Anaerobic cocci, and anaerobic gram-negative bacilli (for
example, Bacteroides species).
3-Metronidazole is the drug of choice for the treatment of
pseudomembranous colitis caused by the anaerobic, gram-positive
bacillus Clostridium difficile and is also effective in the treatment of
brain abscesses caused by these organisms.
Mechanism of action:
Some anaerobic protozoal parasites (including amebas) possess
electron-transport proteins that participate in metabolic electron
removal reactions. The nitro group of metronidazole is able to
serve as an electron acceptor, forming reduced cytotoxic
compounds that bind to proteins and DNA, resulting in cell death.
Pharmacokinetics:
1-Metronidazole is completely and rapidly absorbed after oral
administration .
Note: For the treatment of amebiasis, it is usually administered
with a luminal amebicide, such as iodoquinol or paromomycin. This
combination provides cure rates of greater than 90 percent.
2-Metronidazole distributes well throughout body tissues and
fluids. Therapeutic levels can be found in vaginal and seminal
fluids, saliva, breast milk, and cerebrospinal fluid (CSF).
Adverse effects:
1-The most common adverse effects are those associated with the
gastrointestinal tract:
including nausea, vomiting, epigastric distress, and abdominal
cramps , An unpleasant, metallic taste is often experienced.
2-Other effects include oral moniliasis (yeast infection of the
mouth) .
3-Rarely, neurotoxicologic problems, such as dizziness, vertigo,
and numbness or paresthesias in the peripheral nervous system.,
The latter are reasons for discontinuing the drug.
Tinidazole: Tinidazole is a second-generation nitroimidazole that
is similar to metronidazole in spectrum of activity, absorption,
adverse effects and drug interactions.
Tinidazole is as effective as metronidazole, with a shorter course
of treatment, yet is more expensive than generic
metronidazole.
2-Luminal amebicides
After treatment of invasive intestinal or extraintestinal amebic
disease is complete, a luminal agent, such as iodoquinol,
diloxanide furoate, or paromomycin, should be administered for
treatment of asymptomatic colonization state.
Iodoquinol:
Iodoquinol a halogenated 8-hydroxy quinolone, is amebicidal
against E. histolytica, and is effective against the luminal
trophozoite and cyst forms.
Paromomycin:
Paromomycin, an aminoglycoside antibiotic, is only effective
against the intestinal (luminal) forms of E. histolytica, because it is
not significantly absorbed from the gastrointestinal tract.
3- Systemic amebicides
These drugs are useful for treating liver abscesses or intestinal
wall infections caused by amebas.
1-Chloroquine:
Chloroquine is used in combination with metronidazole and
diloxanide furoate to treat and prevent amebic liver abscesses. It
eliminates trophozoites in liver abscesses, but it is not useful in
treating luminal amebiasis. Chloroquine is also effective in the
treatment of malaria.
2-Emetine and dehydroemetine:
Emetine and dehydroemetine are alternative agents for the
treatment of amebiasis. They inhibit protein synthesis by blocking
chain elongation. Intramuscular injection is the preferred route.
Exercise one: select appropriate treatment for these different
conditions of amoeba infections?
1-asymptomatic carrier state?
2-diarrohea or amoebic dysentery ?
3- liver abscess?
Chemotherapy for Leishmaniasis
the exact mechanism of action has not been determined. Evidence
for inhibition of glycolysis in the parasite at the
phosphofructokinase reaction has been found. Because it is not
absorbed on oral administration, sodium stibogluconate must be
administered parenterally.
Drugs for the Treatment of Nematodes:
1-Mebendazole
Mebendazole a synthetic benzimidazole compound, is effective
against a wide spectrum of nematodes.
It is a drug of choice in the treatment of infections by:
1- whipworm (Trichuris trichiura).
2- pinworm (Enterobius vermicularis).
3-hookworms (Necator americanus and Ancylostoma duodenale).
4-roundworm (Ascariasis lumbricoides).
Mechanism of action
Mebendazole acts by binding to and interfering with the assembly
of the parasites' microtubules and also by decreasing glucose
uptake. Affected parasites are expelled with the feces..
2-Pyrantel pamoate
Pyrantel pamoate along with mebendazole, is effective in the
treatment of infections caused by roundworms, pinworms, and
hookworms .
Pyrantel pamoate is poorly absorbed orally and exerts its effects in
the intestinal tract.
Mechanism of action
It acts as a depolarizing, neuromuscular-blocking agent, causing
persistent activation of the parasite's nicotinic receptors. The
paralyzed worm is then expelled from the host's intestinal tract.
3-Thiabendazole
Thiabendazole another synthetic benzimidazole, is effective
against:
1- strongyloidiasis caused by Strongyloides stercoralis
(threadworm)
2-cutaneous larva migrans,
3- early stages of trichinosis (caused by Trichinella spiralis.
Mechanisim of action
Thiabendazole, like the other benzimidazoles, affects microtubular
aggregation..
4-Ivermectin
Ivermectin :is the
onchocerciasis.
drug
of
choice
for
the
treatment
of
5- Diethylcarbamazine
is used in the treatment of filariasis because of its ability to
immobilize microfilariae and render them susceptible to host
defense mechanisms.
Drugs for the Treatment of Trematodes
1-Praziquantel
Trematode infections are generally treated with praziquantel. This
drug is an agent of choice for the:
1-treatment of all forms of schistosomiasis and other trematode
infections
2-cestode infections like cysticercosis.
Mechanism of action:
Permeability of the cell membrane to calcium is increased, causing
contracture and paralysis of the parasite.
Drugs for the Treatment of Cestodes
1-Niclosamide
Mechanism of action:
Niclosamide is the drug of choice for most cestode (tapeworm)
infections. Its action has been ascribed to inhibition of the
parasite's mitochondrial phosphorylation of adenosine diphospate,
which produces usable energy in the form of adenosine
triphospate.
2-Albendazole
Albendazole is a benzimidazole that, like the others, inhibits
microtubule synthesis and glucose uptake in nematodes. Its
primary therapeutic application, however, is in the treatment of
cestodal infestations, such as cysticercosis (caused by Taenia
solium larvae) and hydatid disease (caused by Echinococcus
granulosis).
Study Questions
Choose the ONE best answer.
37.1 A 48-year-old immigrant from Mexico presents with seizures
and other neurologic symptoms. Eggs of Taenia solium are found
upon examination of a stool specimen. A magnetic resonance
image of the brain shows many cysts, some of which are calcified.
Which one of the following drugs would be of benefit to this
individual?
A. Ivermectin.
B. Pyrantel pamoate.
C. Albendazole.
D. Diethylcarbamazine.
E. Niclosamide.
Correct answer = C. The symptoms and other findings for this
patient are consistent with neurocysticercosis. Albendazole is
the drug of choice for the treatment of this infestation. The
other drugs are not effective against the larval forms of
tapeworms.
37.2 A 56-year-old man from South America is found to be
parasitized by both schistosomes and Taenia solium the pork
tapeworm. Which of the following anthelmintic drugs would be
effective for both infestations?
A. Albendazole.
B. Ivermectin.
C. Mebendazole.
D. Niclosamide.
E. Praziquantel.
Correct answer = E. Praziquantel is a primary drug for the
treatment of trematode and cestode infestations. Although
albendazole is effective in cysticercosis, it is not active
against flukes, and this patient has no evidence of
cysticercosis. Niclosamide is also active against tapeworms
but has no activity against blood flukes.