ANTI PROTOZOAL AGENTS

Introduction
• Protozoans are unicellular eukaryotic organisms

• Responsible for several serious human diseases:

ameobiasis, Chaga’s disease, malaria, African
sleeping sickness, leishmaniasis, and toxoplasmosis.

• Type of immune response that develops depends (in

part) on the location of the parasite in the host.
• Bloodstream: humoral antibody most effective.
• Intracellular: cell-mediated immune reactions.
 Antiprotozoal drugs

Drug that destroys protozoa

or inhibits their growth and
the ability to reproduce.
•Antiprotozoals are drugs to treat infections caused by single cell organisms
called protozoa , such as amoebas.
•Protozoal infection transmission can be person to person infection of
contaminated water or food, direct contact with a parasite, a mosquito or tick.
• Protozoal disease specially malaria, leishmaniasis and chaga’s disease, are
major cause of mortality in various tropical and subtropical regions
 AMOEBIASIS

It is the cyst form that is responsible for transmission of the

disease.

Amoebiasis is a disease of
the large intestine caused
by Entamoeba histolytica
.
Life Cycle of Amoeba
Life Cycle of Amoeba
 (from Ipecacuanha), less toxic than the parent
Dehydroemetine
emetine, is claimed to be the most effective tissue amoebicide.

Metronidazole,
a nitroimidazole, is the drug of choice in the
treatment of extraluminal amoebiasis. It kills trophozoites but not
cysts of E. histolytica and effectively eradicates intestinal and
extraintestinal tissue infections. It has anaerobic
antibacterial activity and antihelicobacter activity too.
It is an enzyme inhibitor.
Tinidazole appears
to have similar activity and a lesser toxicity
profile than metronidazole, and it offers simpler dosing regimens.
AFRICAN TRYPANOSOMIASIS (SLEEPING DISEASE)

It is caused by the hemoflagellates Trypanosoma bru-

cei rhodesiense and Trypanosoma brucei gambiense.
The organisms are transmitted by bites of tsetse flies
(genus Glossina), which inhabit shaded areas along
streams and rivers. The largest number of cases is
in the Congo. Annual incidence estimates are about
100 000 cases and 48 000 deaths.
American Trypanosomiasis (Chagas’ Disease)
is caused by Trypanosoma cruzi.
African trypanosomiasis – treatment:
Suramin or pentamidine is effective during
the early stages but not for the later
neurological manifestations for which
melarsoprol should be used. Eflornithine
is effective for both early and late stages.

.
Chagas Disease
Toxoplasmosis.
Toxoplasmosis

The definitive hosts are cats. Humans are

infected after ingestion of cysts in raw or under-
cooked meat, ingestion of oocysts in food or water
contaminated by cats, transplacental transmission
of trophozoites or, rarely, direct inoculation of
trophozoites via blood transfusion or organ
transplantation.
Human Trichomoniasis
(Metronidazole or tinidazole
is effective)
Human trichomoniasis caused by Tr. vaginalis,
seen in both females and males. It is usually trans-
mitted by coitus and is sometimes asymptomatic.

The symptomatic condition in females may take the

form of a severe vaginitis associated with discharge,
burning, and pruritus.

In males it may produce urethritis, enlargement of

the prostate, and epididymitis.
Leishmaniasis
Leishmaniasis is a zoonosis.

•Visceral leishmaniasis (kala azar) is caused mainly

by Leishmania donovani in the Indian subcontinent
and East Africa. Treatment:
Sodium stibogluconate or meglumine antimoniate;
resistant cases may benefit from combining
antimonials with allopurinol, pentamidine,
paromomycin, or amphotericin B.
Pneumocystis

Pneumocystis carinii, the causative agent

of interstitial plasma cell pneumonia,
which can also cause extrapulmonary
disease in immunocompromised
patients (AIDS, etc) .

Treatment:
Co-trimoxazole: i.v./p.o. in high daily doses
 Giardiasis

It is a common infection of
the human small intestine with
the protozoan Giardia lamblia, spread via
contaminated food or water, or by direct
person-to-person contact.
Treatment:
Metronidazole, mepacrine, or tinidazole
Classification of Antiprotozoal Drugs

Tinidazole, Ornidazole

1-(2-hydroxy-1-ethyl)-2-methyl-5-nitroimi
dazole

Ornidazole
1-chloro-3-(2-methyl-5-nitro-1H-imidazol-1-yl)propan-2-ol
 Classification of Antiprotozoal Drugs
2. Acetamide Derivatives: Eg.Diloxanide

2-dichloro-N-(4-hydroxyphenyl)-N-
methylacetamide

Diloxanide

3. Halogenated 8-hydroxyquinolines: Eg. Iodoquinol

Diiodohydroxyquinoline (Iodoquinol)
 Classification of Antiprotozoal Drugs
4. Diamidines Eg. Pentamidine Isethionate

Pentamidine Isethionate

bis(2-hydroxyethane-1-sulfonic acid); 4-{[5-(4-

carbamimidoylphenoxy)pentyl]oxy}benzene-1-carboximidamide

Pentamidine Isethionate
Eg.Atovaquone

2-hydroxy-3-[(1r,4r)-4-(4-chlorophenyl)cyclohexyl]-1,4-dihydronaphthalene-1,4-
dione
Classification of Antiprotozoal Drugs

6. Miscellaneous Agents. Eg. Eflornithine

(RS)-2,5-diamino-2-(difluoromethyl)pentanoic acid

Eflornithine
 NITRO IMIDAZOLES

Nitroimidazoles have therapeutic uses as

anaerobic antibacterials and antiprotozoal
agents.

Metronidazole, tinidazole and ornidazole are the main

synthetic agents of therapy for invasive amoebiasis
 Metronidazole
Metronidazole: mixed synthetic agents effective for both intestinal and systemic
amoebiasis.

5-nitroimidazoles are
a well-established group of antiprotozoal and antibacterial agents that inhibit the
growth of both anaerobic bacteria and certain anaerobic protozoa, such as
Trichomonas vaginalis, Entamoeba histolytica and Giardia lamblia.
Metronidazole
Metronidazole
Synthesis of Metronidazole
 Metronidazole

Mixed Amoebicide: effective for both intestinal and

systemic forms of amoeba

Drug of Choice

•Metronidazole 500 mg BD, along with a proton pump inhibitor

BD and clarithromycin BD
Metronidazole
 Use of Tinidazole
Metronidazole: mixed synthetic agents
effective for both intestinal and systemic
amoebiasis.

• A nitroimidazole antitrichomonal agent

effective against Trichomonas vaginalis
• Effective against Entamoeba histolytica
• Effective against and Giardia lamblia
infections.
 Use of Ornidazole
Ornidazole: mixed synthetic agents effective
for both intestinal and systemic amoebiasis.

• Ornidazole has been used in trials studying

the prevention of Elective Colorectal Surgery.
 Use of Diloxanide
• Diloxanide is a luminal amoebicide: active only against
intestinal forms of amoeba.
• Diloxanide (as Diloxanide furoate) is an anti-protozoal
drug used in the treatment of Entamoeba histolytica
and some other protozoal infections.
• Diloxanide is used alone as a primary agent in the
treatment of asymptomatic (cyst passers) intestinal
amoebiasis caused by Entamoeba histolytica.
• Diloxanide may also be used concurrently, or
sequentially, with other mixed agents such as the
nitroimidazoles (eg. metronidazole) in the
treatment/eradication of invasive or extraintestinal
forms of amoebiasis.
 Use of Iodoquinol
• Diiodohydroxyquinoline, also known as
iodoquinol, is a quinoline derivative that can
be used in the treatment of amoebiasis.
 Use of Pentamidine

• Pentamidine is also used as a prophylactic against

Pneumocystis carinii pneumonia (PCP) in patients receiving
chemotherapy and in some patients who have undergone
organ transplantation, as they also have a depressed
immune system as a direct side-effect of the drugs used.
The mortality of untreated PCP is very high.
• Additionally, pentamidine has good clinical activity in
treating leishmaniasis, and yeast infections caused by the
organism Candida albicans.
• Pentamidine is also used as a prophylactic antibiotic for
children undergoing treatment for leukemia.
 Use of Atovaquone
• For the treatment or prevention
of Pneumocystis carinii pneumonia in patients
who are intolerant to trimethoprim-
sulfamethoxazole (TMP-SMX).
 Use of Eflornithine
• Treatment of meningoencephalitis,
trypanosoma bruci gambiense infection.
 SAR of Metronidazole

Ornidazole

• Imidazole ring and nitro group is essential for anti protozoal activity. Nitro group
partcipates in endogenous reduction reaction as electron acceptor.
• Tinidazole and ornidazole have different side chains at the 1 position, do not differ
markedly in their antimicrobial activity.
• Small alkyl groups at position-2 is preferred eg:methyl group.Modifications at the 2
position, however, are known to interfere with both the activity and the microbial
spectrum.
Choice of Drugs for Protozoal
Infections