Antiamebic

CHEMOTHERAPY OF AMEBIASIS

Amebic infection is caused by Entamoeba histolytica. Amebic infection is called amebiasis or amebic dysentery. It is an infection of the intestine that may be acute or chronic in nature and either symptomatic or asymptomatic. Symptomatic amebiasis is characterized by mild diarrhea to fulminating dysentery. In severe condition or unattended amebiasis may also affect another physiological system of the body. Amebiasis in the liver is called hepatic amebiasis and amebiasis outside liver is called extrahepatic amebiasis.

Entamoeba histolytica is unicellular Protozoal Cells. Protozoal cells are eukaryotic cells. Their metabolic processes are very close to human cells metabolic processes. Thus antiprotozoal drugs are very toxic to human cells. E. histolytica exists in two forms i.e. trophozoites and cysts. Usually, patients suffering from symptomatic amebiasis carry trophozoites and asymptomatic patients carry cysts. Antiamebic drugs are effective against trophozoites.

Life cycle of Entameba histolytica

There are two stages of life cycle of Entameba histolytica

·         Trophozoites (Metabolically active stage)

·         Cysts (Metabolically inactive stage)

Cysts survive outside the human body in an inactive form for a longer duration. Trophozoites cannot survive outside the human body. Ameba cysts contaminate food through human feces. Cysts enter into human body through contaminated water and food. Cyst releases trophozoites inside human intestine. Trophozoites feed on intestinal flora, undergoes multiplication, invade intestinal mucosa, form ulcer on large intestinal mucosa wall and then invade physiological systems of human body. Inside rectum trophozoites form a cyst and excreted in feces.

Classification of antiamebic drugs:

Antiamebic drugs can be divided into following three classes, depending upon their site of action

· Luminal Antiamebic Drugs: (Luminal Amebicides): Diloxanide furoate, Diiodohydroxyquine, Iodoquinol, Clefamide, etc. They are effective against ameba in the intestinal lumen. They are amebicide do not effective against ameba present in intestinal mucosa wall or another physiological system. They are used to treat asymptomatic amebiasis or mild symptomatic amebiasis.

However, they are also used in combination with systemic amebicides or mixed amebicides to eradicate the infection

· Systemic amebicides or Tissue amebicides: Emetine, Dihydroemetine, Chloroquine. They act as amebicide in the intestinal wall, liver, and other extrahepatic tissues. But they are not effective against ameba present in intestinal lumen However, they are not a drug of choice to treat amebiasis due to their toxic effect.

·    Mixed Amebicides: Metronidazole, Tinidazole, Secnidazole, Ornidazole etc. They are effective against both luminal amoeba and tissue ameba. Luminal amebicides are used with mixed amebicides to eradicate the amebic infection.

Diloxanide furoate: It is dichloroacetamide derivatives. It is administered by oral route. 90% of diloxanide is absorbed. It is hydrolyzed inside mucosal cells. 10 % unabsorbed diloxanide furoate present in lumen produce the amebicidal effect. Absorbed hydrolyzed diloxanide is distributed in tissue vert poorly. Thus they cannot produce a therapeutic effect in tissues. Metabolised diloxanide furoate is excreted in urine.

It produces mild adverse effects like flatulence, dryness of mouth, pruritis, and urticaria. It is contraindicated in pregnant women and children below two years.

Emetine and dehydroemetine: They are Ipecac alkaloid and highly toxic. Thus, they have been replaced by other more effective and safer amebicides like nitroimidazole derivatives. Emetine and dehydroemetine are used in nitroimidazole failure. However, dehydroemetine is less toxic than emetine.

They are administered by the intramuscular or subcutaneous route to avoid GIT disturbance. They concentrate in liver, lungs, and kidney. They are also slowly metabolized and slowly excreted in urine. Thus they produce a cumulative effect. Their half-life is about 5 days. The patient should be under close supervision of medical practitioner during drug administration and treatment.

They are effective against trophozoites in tissues not in the intestinal lumen. They are effective against trophozoites in tissues not in the intestinal lumen. They block polypeptide chain elongation thus they block protein synthesis to produce amebicide effect.

Adverse Effects: Nausea, Cardiotoxicity, Neuromuscular weakness, dizziness, and rashes.

Chloroquine: It is systemic amebicide (Tissue Amebicide). It is rapidly absorbed from GIT and distributed throughout the body but maximum concentration is found in liver. Thus it is not effective against E. histolytica trophozoites in the intestine and very effective against E. histolytica trophozoites in the liver.

Therapeutic Uses: It is used in metronidazole failure in the treatment of amebiasis. It is used in combination with metronidazole and diloxanide furoate to treat amebiasis and hepatic abscess. It is also useful in invasive intestinal amebiasis.

Metronidazole: It is 5 nitroimidazole derivative. It is rapidly and completely absorbed from GIT. Food decreases the rate of metronidazole absorption but it does not affect the extent of its absorption. Metronidazole is completely absorbed even in presence of food in GIT. It is well distributed throughout the body but its concentration in the liver is much more than any other tissues. It is metabolized in the liver by oxidation followed by glucuronidation. Metabolites are excreted in urine.

Mechanism of action: It kills E. histolytica trophozoites and also anaerobic organism including anaerobic bacteria. It also produces a toxic effect to anoxic and hypoxic cells. (Cells not oxygenated is called anoxic cell and Cells not adequately oxygenated is called hypoxic cells)

Its penetration into bacterial cells and protozoal cells is faster than mammalian cells/ It freely penetrates into bacterial cells and protozoal cells. Inside cells, 5-nitro group of metronidazole acts as electron receptor and metronidazole undergo reduction reaction. Reduced form is a cytotoxic compound that binds to protein and DNA of cells. It produces breakage of DNA strands and death of cells. It has also the radisensitization effect on hypoxic tumor cells.

It does not penetrate freely into mammalian cells thus its toxic effect on mammalian cells is less than on microbial or protozoal cells.

Antibacterial Spectrum: It acts against parasites like E. histolytica, Trichomonas vaginitis, Giardia lamblia, Balantidium collie. It is also effective against anaerobic bacteria both gram –ve and gram +ve.

Adverse effects:

GIT: Nausea, vomiting, epigastric distress, abdominal cramp, metallic taste, yeast infection in the mouth (Oral moniliasis)

CNS: Seizure and peripheral neuropathy associated with numbness in extremity. These are most serious side effects.

Hematological: Reversible leukopenia.

Genito Urinary: Deep red-brown urine color. Dysuria (Pain, discomfort, burning during urination), cystitis, polyurea(Abnormally large volume of urine) etc.

Drug Interaction: It should not be consumed with alcoholic products. It produces the disulfiram-like effect with alcohol (Antabuse like reaction), abdominal cramp, nausea, vomiting headache, flushing, etc. (Antabuse is the brand name of disulfiram that is used to treat alcoholism by producing nausea and unpleasant effects). If it is administered with disulfiram, it produces an acute psychotic reaction (Confusional state)

Cimetidine blocks metronidazole metabolism. Thus cimetidine precipitate metronidazole side effects,

It is also contraindicated during pregnancy, especially in the first trimester.

Tinidazole: It has a longer duration of action than metronidazole due to the slow rate of metabolism.

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