ANTIPROTOZOAL AGENTS

Protozoal diseases are highly prevalent in tropical third countries

where they infect both human and animal populations. Some of the protozoan enter and grow indide the body and cause some protozoal

disease

like

Amoebiasis,

Leishmaniasis,

Trypnosomiasis,

Trichomoniasis Toxoplasmosis and giardiasis Introduction about protozoal disease

1. Amoebiasis
2. Leishmaniasis 3. Trypnosomiasis 4. Trichomoniasis

5. Giardiasis
6. Toxoplasmosis

1. Amoebiasis It caused by the protozoan Entamoeba histolytica. Water born disease Infections generally remain confined to the mucous membrane of the large intestine, where they may give rise to dysentery
Amoebae may locate especially in the liver. The chemotherapy of amoebiasis must provide drugs to treat both the intestinal and extra intestinal forms of the disease. It exist in two forms a. Trophozoites- active form responsible for acute attack

b. Cysts-inactive form responsible for spreading of amoebiasis (Cysts-any closed cavity or sac lined by epithelium contains liquid or semisolid or a stage in the life cycle of some parasites)
Intestinal amoebiasis Trophozoites are present in the colon In most infections trophozoites appear to feed on intestinal bacterial flora and multiply in the colonic lumen without causing

any symptoms.
But under certain circumstances trophozoites may get activated in the intestinal mucosa causing lysis and producing dysentery or diarrhea.

They are responsible for amoebic dysentery They produce ulcer in the colon
Some of the trophozoites are converted into cysts Trophozoites and cysts are passed along with stool Trophozoites die soon but cysts survive for several days Water and food contamination the cysts enter the intestine The cyst form of the organisms is ineffective and the infection is

acquired by ingestion of amoebic cysts in food or water contaminated due to handling by such asymptomatic infected person.
This infection usually prevails in the area of poor hygienic conditions and inadequate sanitation.

Extra intestinal amoebiasis

Trophozoites present in intestine migrate to liver via portal circulation and causes amoebic hepatitis and amoebic abscess Acute amoebic dysentery

Amoeba can cause attacks of acute dysentery which is characterized by frequent passing of stool with blood and mucus and
abdominal pain This occurs when the amoebae invade the wall of intestine,

mulitply and cause tissue damage often forming layers and ulcers. Later amoebae may invade the blood vessels and can be carried to
the liver and even to brain Death can occur from liver which can perforate into the lungs.

Chronic amoebiasis
Loss of appetite, abdominal pain intermittent diarrhoea Amoebic carriers Many infected persons who pass the cysts in the stool but they do not

suffer from dysentery. They remain symptom less.

They are responsible for spreading the infection. Clasification 1. Luminal amoebicides

They are effective against the organism present in the bowel lumen Highly effective in eliminating cysts in asymptomatic carriers

Eg. Diloxanide furoate, Iodoquinol, clioquinol

2. Luminal trophozoitocidal agents

Eg.

Attack intestinal trophozoites Effectively used to treat invasive intestinal amoebiasis

Metronidazole, erythromycin tinidazole, paramycin tetracycline and

3. Systemic amoebicides They are not acting locally in the intestine When trophozoites spread into liver, brain or lungs these drugs may be used to treat extraintestional manifestations of invasive

amoebiasis

2. Leishmaniasis It is caused by protozoa belonging to the genus leishmani. Chronic tropical disease caused by various flagellate protozoa of
the genus leishmani These disease are widespread in tropical areas of Africa and south and central American They are 3 forms of leishmaniasis a. Visceral leishmaniasis

b. Cutaneous leishmaniasis c. Mucocutaneous leishmaniasis

Visceral leishmaniasis It is caused by protozoa leishmania donovani. It is transmitted by sand flies phelbotomus This disease is found in Africa , China, South Africa In India it is found in Assam, Orissa and bengal It is characterized by irregular fever, enlargement of spleen, anaemia and leucopenia Diagnosis Leishmania bady is found in peripheral blood or in the aspirate obtained by sternal or splenic or liver or lymph node puncture Blood culture on media is more certain but time consuming process Classification of drugs 1. Pentavalent antimony compounds: Ethyl stibamine 2. Diamidine derivatives: Dihydroxy stibamidine

3. Trypnosomiasis The disease is caused by protozoan parasite belonging to genus trypnosomiasis The principle disease in humans sleeping sickness can be broadly classified into two main groups African sleeping sickness caused by T. gambiense. Early stage is manifested by fever, anaemia and edema Later is invasion of CNS occur mental and physical lethargy tremors, convulsions, coma and death 1. African Trypnosomiasis The disease is caused by protozoan parasite trypnosoma gambiense and transmitted by wood land flies 2. South American Trypnosomiasis The disease is caused by protozoan parasite trypnosoma cruzi and transmitted by blood sucking reduvid bugs

Symptoms
Irregular fever Lymph node enlargement Skin eruptions, tremor

Convulsions
Coma and death due to encephalitis

Drugs: pentamidine isethionate, suramin sodium 4. Trichomoniasis

Veneral disease caused by the flagellated protozoan Trichomonas

Vaginalis in man. Trichomonas Foetus in cattles

It is not generally considered serious it can cause serious physical discomfort and sometimes has a chilling effect on sexual relations

T. are unicellular, flagellated protozoal parasites Most of them are nonpathogenic in nature Males are asymptomatic carriers but female often develop severe vaginalis (characterised by a frothy pale yellow discharge) and cervicitis It is caused by protozoan parasite trichomonas vaginalis Symptoms Thin greenish yellow frothy discharge from vagina and burning sensation in vagina. Infection in male is always symptom less Males are carriers. They transmit the disease to females Therefore treatment for both wife and husband is necessary Drugs: Tinidazole, Metronidazole, Quinidochlor, furazolidone

5. Giardiasis The disease is caused by protozoan parasite giardia lamblia. It is transmitted from man to man by fecal contamination of food and
water Symptoms Diarrohoea, Abdominal pain, Loss of appetite, Weight loss

Drugs: Tinidazole, Metronidazole, furazolidone, Phanquone, chloroquine

and quinidochlor are useful in giardiasis

6. Toxoplasmosis It is caused by the ingestion of oocysts of Toxoplasma gondi from the

feces of infected cats or ingestion of cysts affected raw meat

Clinical Classification

i)

Drugs used in intestinal amoebiasis:

Amide: Diloxanide furoate 8-Hydroxyquinolines:Quiniodochlor (Iodochlorhydroxyquin,

Clioquinol), Diiodohydroxyquin, Broxyquinoline Antibiotics: Tetracyclines, Nifurtimox

ii) Drugs used in extra intestinal amoebiasis: Chloroquine

iii) Drugs used for both intestinal and extra intestinal Nitro imidazole:
Alkaloids:

Mebendazole, Albendazole,
Metronidazole, Tinidazole Emetine, Dehydroemetine

Chemical Classification i) Emetine group: Emetine, Dehydroemetine

ii) Halogenated oxyquinolines; Quiniodochlor , Didoquine

iii) 4-amino quinolines: Chloroquine iv) Antibiotics: Tetracycline, paramomycin, fumagillin and Nifurtimox
v) Nitro imidazole: Metronidazole, Tinidazole

vi) Miscellaneous: Diloxanide, Phanquone

1. Metronidazole (flagyl and metrogyl)

2-methyl-5-nitroimidazole-1-ethanol is the most useful of a

multitude of antiprotozoal nitro imidazole derivatives that have been synthesized in various laboratories throughout the world. Metronidazole was first marketed for the topical treatment of T. vaginalis, vaginitis.

Properties Metronidazole is a pale yellow crystalline substance Sparingly soluble in water. Stable in air, but is light sensitive MOA The effectiveness is due to the presence of nitro group which participate in endogenous reduction. It act as an artificial electron acceptor The nitro group accepts electrons from electron transport proteins and diverts them from normal energy yielding pathways. Nitro group reduced to amine group. This causes interference in the carbohydrate metabolism and nucleic acid synthesis, It also binds with cytoplasmic production of susceptible cells

After entering the microorganism by diffusion, it is reduced to

intermediate compounds which cause cytotoxicity, probably by damaging DNA. The reactive intermediate formed in the parasital reduction of the 5nitro group of metrinidazole covalently binds to the DNA of the

parasite and causes a loss of the helical structure of DNA, strand breakage and an accompanying impairment its function resulting in cell death.
Its selectively high activity against anaerobic organisms interference with electron transport form NADPH or other reduced substrates. It inhibit cell mediated immunity, to induce mutagenesis and to cause radio sensitization.

Uses It is a nitroimidazole derivative that is employed for the treatment of amoebiasis Cidal activity against protozoa including Giardia lamblia It is sensitive to many anaerobic bacteria It does not affect aerobic bacteria Acute amoebic dysentery Amoebic hepatitis Therapy for American trypanosomiasis with oral benznidazole requires several weeks and is frequently accompanied by adverse effects such as peripheral neuropathy, bone marrow depression and allergic reactions. Giardiasis 200mg TDS for 7days Trichomonas vaginitis 200-400mg for 7 days

Anaerobic infections It may occur after pelvic surgery, appendices etc Ulcerative gingivitis 200-400 mg TDS combine with penicillin, tetracycline Guinea worm infestation (Dragunculosis) 200-400 mg for 7 days TDS Adverse effect

Nausea, metallic taste, abdominal cramps are the most common Prolonged administration peripheral neuropathy and CNS effects. Seizures have followed very high doses. Thromboflebitis of injected vein occur if the solution is not well diluted Urethral burning

2. Diloxanide (furamide)
Furamide or eutamide is the 2- furoate ester of 2,2-dichloro-N-methyl acetanilide.

The discovery that various alpha, alpha-dichloro acetamides possessed amebicidal activity in vitro. Properties It is a white crystalline powder Slightly soluble in water Furoate ester more soluble than diloxanide

MOA Interfere with protein synthesis Interfere with the activity of some essential enzymes of protozoa Uses
Orally 500-mg tablets and may be obtained in the United States from the Centers for Disease Control in Atlanta Direct amoebicidal action. Effective against cyst and trophozites. Diloxanide itself and many of its esters are also active and drug metabolism studies indicate that hydrolysis of the ester is required for the amebicidal effect. Nonpolar esters of diloxanide are more potent than polar ones. It is used in the treatment of asymptomatic carriers of E. histolytica. Its effectiveness against acute intestinal amebiasis or hepatic abscesses. Chronic amoebiasis Amoebic carriers

3. Emetine and Dehydro emetine

The alkaloids emetine and dehydro emetine are obtained by isolation from cephaelis Ipecacuaanha.

Properties They occur as levorotatory, light-sensitive white powders insoluble in water.

The alkaloids readily form water-soluble salts. Solutions of the hydrochloride salts intended for intramuscular injection should be adjusted to pH 3.5 and stored in light-resistant containers.

MOA It is highly effective against trophozoites Ineffective against cyst Emetine prevent protein synthesis It also direct lethal action on the parasite It is an amoebicidal drug

Uses Acute amoebic dysentery

Amoebic hepatitis Liver fluke infestation Toxicity Cumulation

Pain at the site of injection Tachycardia Hypotension

Less toxic than emetine

Dehydroemetine
This is a semi synthetic preparation. Less irritant orally Less cumulative Less toxic than emetine Toxicity

It causes a high frequency of gastrointestinal distress (especially nausea and diarrhea), cardiovascular effects (hypotension and arrhythmias) and neuro muscular effects (pain and weakness). A lower incidence of cardiotoxicity has been associated with the use of dehydroemetine (Mebadin) available from the Centers for Disease Control, which is also amebicidal. Uses Used to treat dysentery and fluke infestations such as fascioliasis and paragonimiasis.

4. Nifurtimox
Nifurtimox is 4-((5-nitrofurfurylidene)amino1-3-methyl morpholine 1,1-dioxide. thio

The observation that various derivatives of 5-nitrofuraldehyde possessed, in addition to their antibacterial and antifungal properties
Significant and potentially useful antiprotozoal activity eventually led to discovery of particular nitrofurans with anti trypanosomal activity The most important of such compounds is nifurtimox effectiveness

against T. cruzi, the parasite responsible for South American trypanosomiasis. Clinically used in the treatment for both acute and chronic forms
of the disease.

It is available in the United States from the Centers for Disease

Control. Adverse reaction The drug is poorly tolerated, with a high incidence of nausea,

vomiting, abdominal pain, and anorexia reported. Symptoms of central and peripheral nervous system toxicity also frequently occur with nifurtimox.