ANTIPROTOZOAL

AGENTS
By
Rushikesh Diware
Introduction

• protozoal diseases are of minor importance

• they infect both human and animal populations

• causing suffering, death, and enormous economic hardship.

• Protozoal diseases that are found are malaria, amebiasis, giardiasis,

trichomoniasis, toxoplasmosis, a direct consequence of the AIDS
epidemic, P. carinii pneumonia (PCP).
AMEBIASIS
• amebiasis is tropical disease

• occurred in area of sanitation is poor

• amebiasis has been estimated to be as high as 20% of the population.

• The causative organism, Entamoeba histolytica, can invade the wall of the colon or other parts of the body (e.g., liver,

lungs, skin).

• An ideal chemotherapeutic agent would be effective against both the intestinal and extraintestinal forms of the parasite.

• Amoebiasis has a worldwide distribution (over 50 million people suffer invasive disease

• It is endemic in most parts of India (about 15% people are infected)

• Poor environmental sanitation and low socio-economic status are important factors in the spread of the disease, which

occurs by fecal contamination of food and water.

• Other protozoal species that colonize the intestinal tract and cause enteritis and diarrhea are
• Balantidium coli

• flagellates, G. lamblia

• Cryptosporidium spp. Balantidiasis

• responds best to tetracycline.

• Metronidazole and iodoquinol may also be effective.

• Giardiasis may be treated effectively with furazolidone, metronidazole, or the

• antimalarial drug quinacrine (Chapter 7). Cryptosporidiosis

• is normally self-limiting in immunocompetent patients and

• is not normally treated. The illness can be a serious problem

• in AIDS patients because no effective therapy is currently

• Amebicides effective against both intestinal and extraintestinal forms of the
disease

• Toxic alkaloids emetine and dehydroemetine, the nitroimidazole

• derivative metronidazole, and the antimalarial agent chloroquine

• A second group effective only against intestinal forms of the disease includes the
aminoglycoside antibiotic paromomycin,

• the 8-hydroxyquinoline derivative iodoquinol,

• the arsenical compound carbarsone, and diloxanide.

GIARDIASIS
• Caused by Giardia lamblia is a flagellate protozoon

• infects children and adults by oro-faecal contamination

• mostly lives as a commensal in the intestine.

• Invades the mucosa

• causes acute watery short duration diarrhoea with foul smellling stools, gas and abdominal
cramps.

• If untreated, it may pass on to chronic diarrhoea with greasy or frothy stools but no blood or
mucus.

• Many drugs useful in amoebiasis are also effective in giardiasis.

Trichomoniasis
• caused by the flagellated protozoan Trichomonas vaginalis,

• can cause serious physical discomfort.

• Causes vulvovaginitis.

• It is a common sexually transmitted disease affecting ~ 10% sexually active

women.

• Several drugs are partly effective by vaginal application, but may not entirely
clear the infection; recurrences are frequent

• Repeat courses are required.

Pneumocystis pneumonia (PCP)

• P. carinii is an opportunistic pathogen

• may colonize the lungs of humans and other animals
• cause pneumonia.
• The organism has long been classified as a protozoan, but recent RNA
evidence suggests that it may be more closely related to fungi.
• PCP were known to occur in premature, undernourished infants and
in patients receiving immunosuppressant therapy.
• at least 60% and possibly as high as 85% of patients infected with HIV
develop PCP during their lifetimes.
 LEISHMANIASIS
• Visceral leishmaniasis (VL; kala-azar) caused by Leishmania donovani

• occurs in several tropical and subtropical regions of the world.

• 0.3 million cases of VL occur annually worldwide with > 20,000 deaths each year.

• 90% of the cases occur in India, Brazil, Ethiopia, Kenya, Somalia and Sudan

• leishmaniasis is prevalent in Bihar, West Bengal, Jharkhand and eastern UP; Bihar
contributes 50% cases that occur world over.

• In treating VL, the geographical location is important

• transmitted by the bite of the female sandfly phlebotomus

• disease of the economically poor class,

• affected areas are underdeveloped

• The currently used drugs for treatment of VL are:

• 1. Sodium stibogluconate (SSG)

• (or Meglumine antimonate—in French speaking

• countries of latin and south America)

• 2. Amphotericin B (AMB)

• 3. Miltefosine

• 4. Paromomycin.
 Toxoplasmosis

• Toxoplasma gondii family Trypanosomidae is an intracellular protozoan

• best known for causing blindness in neonates.

• the disseminated form of the disease which the lymphatic system, skeletal
muscles, heart, brain, eye, and placenta may be affected,

• become increasingly prevalent in association with HIV infection.

• A combination of the antifolate pyrimethamine and the sulfa drug

• sulfadiazine constitutes the most effective therapy for toxoplasmosis.

Sleeping sickness

• broadly classified into two main geographic and etiological groups:

• African sleeping sickness caused by Trypanosoma gambiense (West African),

Trypanosoma rhodesiense (East African), or Trypanosoma congolense
• South American sleeping sickness (Chagas disease) caused by Trypanosoma
cruzi. Of the various forms of trypanosomiasis
• Chagas disease is the most serious and generally the most resistant to
chemotherapy.
Classifications

• 1. Nitroimidazole: Metronidazole, Ornidazole, Tinidazole

• 2. Amides: Diloxanide, Nitazoxanide

• 3. 8-Hydroxyquinolones: Idoquinol

• 4. naphthoquinone Darivatives: Atovoquone

• 5. Miscleneoues: Enflornithine
Metronidazole
• Introducedin 1959 for trichomoniasis

• later found to be a highly active amoebicide.

• Broadspectrum cidal activity against anaerobic protozoa, including giardia lamblia

• Many anaerobic and microaerophilic bacteria, such as bact. Fragilis, fusobacterium,

clostridium perfringens, cl. Difficile, helicobacter pylori, campylobacter, peptococci,
spirochetes and anaerobic streptococci are sensitive.

• binds deoxyribonucleic acid and electron-transport proteins of organisms, blocking nucleic

acid synthesis.

• Does not affect aerobic bacteria.

• Clinically significant resistance has not developed among e. Histolytica,

• MOA: activated to highly reactive nitro radical which exerts cytotoxicity. The nitro
radical acts as an electron sink

• Which competes with the biological electron acceptors

• the anaerobic organism for the electrons generated by the pyruvate : ferredoxin
oxidoreductase (PFOR) enzyme pathway of pyruvate oxidation.

• ADR: Anorexia, nausea, metallic taste and abdominal cramp

• cause peripheral neuropathy and CNS effects.

• Uses: T. vaginalis, intestinal and hepatic amebiasis, giardiasis and balantidiasis,

invasive dysentery and liver abscess, Acute necrotizing ulcerative gingivitis (ANUG)
Tinidazole
• Uses: Intestinal amoebiasis, Amoebic liver abscess,
• ADR: upset stomach, bitter taste, diarrhea, and itchiness.
• Ornidazole:
• ADR: rash, itching, hives, swelling of the face, lips, mouth or throat which may
cause difficulty in swallowing or breathing, swelling of the hands, feet or
ankles.
• slowly metabolized—has longer t½ (12–14 hr).
Diloxanide furoate
• highly effective luminal amoebicide
• kills trophozoites responsible for production of cysts.
• weaker amoebicide than its furoate ester.
• No systemic antiamoebic activity is evident despite its absorption
• high (80–90%) cure rate in mild intestinal amoebiasis and in
asymptomatic cyst passers
• MOA: Unkown
• ADR: flatulence, occasional nausea, itching and rarely urticaria.
Pentamidine Isethionate
• use for the treatment of pneumonia caused by the opportunistic
pathogenic protozoan P. carinii,
• a frequent secondary invader associated with AIDS.
• African trypanosomiasis, visceral leishmaniasis
• ADR: heart problems, low blood pressure, low or high blood sugar,
and other blood problems.

• Iodoquinol:
• acute and chronic intestinal amebiasis
• ADR: high incidence of topic neuropathy
Atovaquone
• 3-[4-(4-Chlorophenyl)-cyclohexyl]-2-hydroxy-1,4-naphthoquinone
• 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
• may act as an antimetabolite for the latter and thereby interfere with
the function of electron transport enzymes.
• against P. carinii PCP
• ADR: depression, symptoms of liver disease (such as nausea/vomiting
that doesn't stop, loss of appetite, stomach/abdominal pain,
yellowing eyes/skin, dark urine)
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.
• Myelosuppressive drug that causes high incidences of anemia,
leukopenia, and thrombocytopenia.
• Complete blood cell counts must be monitored during the course of
therapy.
 Anthelmintics
• are drugs used to treat parasitic infections due to worms.

• Worms that are pathogenic to human beings, namely, metazoa

• classified into two types

• Round worms (nematodes) and of flatworms, that is, flukes (trematodes) and tapeworms (cestodes).
Anthelmintics act locally either to expel

• the worms from the gastrointestinal tract or systemically to eradicate the species and the developing
forms of helmintics that invade the organs and tissues

• No cheaper medicines are available for this disease, even now, although the primitive Chinese and
Egyptians have started treating this disease 3500 years ago.
 Classification
• I. Benzimidazoles
Ivermectin (Cardomec, Eqvalan, Ivomec)
• is a mixture of 22,23-dihydro derivatives of avermectins B1a and B1b
• prepared by catalytic hydrogenation.
• members of a family of structurally complex antibiotics
• produced by fermentation with a strain of Streptomyces avermitilis.
• active in low dosage against a wide variety of nematodes and
arthropods that parasitize animals.