Antiprotozoal
agents
• In
the United States and other countries of the temperate zone, protozoal diseases
are of minor importance
• Protozoal
diseases are highly prevalent in tropical Third World countries, where they
infect both human and animal populations
• Cause
suffering, death, and enormous economic hardship
• Protozoal
diseases that are found in the United States are malaria, amebiasis,
giardiasis, trichomoniasis, toxoplasmosis, and, as a direct consequence of the
AIDS epidemic, P. carinii pneumonia (PCP)
• Amebiasis-
Entamoeba histolytica
• Can
invade the wall of the colon or other parts of the body (e.g., liver, lungs,
skin)
• Other
protozoal species that colonize the intestinal tract and cause enteritis and
diarrhea are Balantidium coli and the flagellates, G. lamblia and
Cryptosporidium spp
• Trichomoniasis,
a venereal disease caused by the flagellated protozoan T. vaginalis
• P.
carinii is an opportunistic pathogen that may colonize the lungs of
humans and other animals and, under the right conditions, can cause pneumonia
• Toxoplasma
gondii is an obligate intracellular protozoan that is best known for
causing blindness in neonates
• Various
forms of trypanosomiasis, chronic tropical diseases caused by pathogenic
members of the family Trypanosomidae, occur both in humans and in livestock
• African
sleeping sickness caused by Trypanosoma gambiense (West African), Trypanosoma
rhodesiense (East African), or Trypanosoma congolense; and
• South
American sleeping sickness (Chagas disease) caused by Trypanosoma cruzi
• Chagas
disease is the most serious and generally the most resistant to chemotherapy
• Leishmaniasis
is a chronic tropical disease caused by various flagellate protozoa of the
genus Leishmania
• More
common visceral form caused by Leishmania donovani, called kala-azar,
is similar to Chagas disease
Metronidazole
• Most
useful of a group of antiprotozoal nitroimidazole derivatives that have been
synthesized in various laboratories throughout the world
• First
marketed for the topical treatment of T. vaginalis for vaginitis
• Also
possesses useful amebicidal activity and is, in fact, effective against both
intestinal and hepatic amebiasis
• Other
protozoal diseases as giardiasis and balantidiasis
• It
is particularly active against Gram-negative anaerobes, such as Bacteroides and
Fusobacterium spp
• It
is also effective against Gram-positive anaerobic bacilli (e.g., Clostridium
spp.) and cocci (e.g., Peptococcus, Peptidostreptococcus spp.).
• Because
of its bactericidal action, metronidazole has become an important agent for the
treatment of serious infections (e.g., septicemia, pneumonia, peritonitis,
pelvic infections, abscesses, meningitis) caused by anaerobic bacteria
• Mechanism- reactive
intermediate formed in the microbial reduction of the 5-nitro group of
metronidazole covalently binds to the DNA of the microorganism, triggering the
lethal effect
• Potential
reactive intermediates include the nitroxide, nitroso,
• hydroxylamine,
and amine
• Ability
of metronidazole to act as a radiosensitizing agent
• is
also related to its reduction potential
Mechanism of metronidazole
• Pale
yellow crystalline substance that is sparingly soluble in water
• It
is stable in air but is light sensitive
• 2-hydroxy
metabolite is active; other metabolites are inactive
• Solutions
of metronidazole hydrochloride are unsuitable for intravenous administration
because of their extreme acidity
• Must
be reconstituted with sterile water to yield 5 mL of a solution having a
concentration of 100 mg/mL and a pH ranging from 0.5 to 2.0
• Resulting
solution must then be diluted with either 100 mL of normal saline or 5%
dextrose and neutralized with 5 mEq of sodium bicarbonate to provide a final
solution of metronidazole base with an approximate concentration of 5 mg/mL and
a pH of 6 to 7
Tinidazole
• Approved
by the U.S. Food and Drug Administration (FDA) for the treatment of amebiasis,
giardiasis, and trichomoniasis
• Also
to be highly effective against Helicobacter pylori infections
• Drug
is rapidly and completely absorbed following oral administration and can be
administered with food to reduce GI disturbance
• Mechanism
of action- similar to metronidazole
• Tinidazole
appears to mimic the actions of metronidazole
• Also
effective against some protozoa that are resistant to metronidazole
Ornidazole
• Antibiotic
used to treat protozoan infections
• Antimicrobial
spectrum is similar to that of metronidazole
• It
was first introduced for treating trichomoniasis before being
recognized for its broad anti-protozoan and anti-anaerobic-bacterial capacities
Diloxanide
• 2-furoate
ester of 2,2-dichloro-4-hydroxy-N-methylacetanilide
• It
was developed as a result of the discovery that various ,α–α-dichloroacetamides possessed amebicidal activity in vitro
• Used
in the treatment of asymptomatic carriers of E. histolytica
• White
crystalline powder and is administered orally only as 500-mg tablets
Iodoquinol
• Diiodohydroxyquin is a yellowish to
tan microcrystalline, light-sensitive substance that is insoluble in water
• It
is recommended for acute and chronic intestinal amebiasis but is not effective
in extraintestinal disease
• Because
a relatively high incidence of peripheral neuropathy has occurred with its use,
iodoquinol should not be used routinely for traveler’s diarrhea
Pentamidine Isethionate
• Water-soluble
crystalline salt that is stable to light and air
• Principal
use of pentamidine is for the treatment of pneumonia caused by the
opportunistic pathogenic protozoan P. carinii, a frequent secondary
invader associated with AIDS
• Drug
may be administered by slow intravenous infusion or by deep intramuscular
injection for PCP or in an aerosol form
• Both
the inhalant (aerosol) and parenteral dosage forms of pentamidine isethionate
are sterile lyophilized powders
• Must
be made up as sterile aqueous solutions prior to use by sterile water for
injection
• Common
adverse reactions- cough and bronchospasm (inhalation) and hypertension and
hypoglycemia (injection)
• Used
for the prophylaxis and treatment of African trypanosomiasis. It also has some
value for treating visceral leishmaniasis
• Prophylaxis-
treatment given or action taken to prevent disease
• Because,
Pentamidine rapidly disappears from the plasma after intravenous injection and
is distributed to the tissues, where it is stored for a long period
Atovaquone
• Highly
lipophilic, water-insoluble analog of ubiquinone 6, an essential component of
the mitochondrial electron transport chain in microorganisms
• Structural
similarity between atovaquone and ubiquinone suggests that thereby interfere
with the function of electron transport enzymes
• Originally
developed as an antimalarial drug, but Plasmodium falciparum was found
to develop a rapid tolerance to its action
• Recommended
alternative to trimethoprim-sulfamethoxazole (TMP-SMX) for the treatment and
prophylaxis of PCP in patients intolerant to this combination
• High
fat content, increases atovaquone absorption
• It
is extensively protein bound (99.9%)
• Half-life
of the drug ranges from 62 to 80 hours
• Primary
side effect is gastrointestinal intolerance
Eflornithine
• Used
for the treatment of West African sleeping sickness, caused by Trypanosoma
brucei gambiense
• It
is specifically indicated for the meningoencephalitic stage of the disease
• Eflornithine
is a myelosuppressive drug that causes high incidences of anemia, leukopenia,
and thrombocytopenia
• Complete
blood cell counts must be monitored during the course of therapy
• Supplied
as the hydrochloride salt
• It
may be administered either intravenously or orally
• Approximately
80% of the unchanged drug is excreted in the urine
• Mechanism-
irreversible inactivation of ornithine decarboxylase by eflornithine is
accompanied by decarboxylation and release of fluoride ion
• Enzyme
is involved in the synthesis polyamines which are regulators of growth
processes
Metronidazole- Synthesis
