Anti amoebic Agent

Anti-Amoebic Agent

Compiled by Alok Bains

Introduction

Ameobiasis is a protozoal infection caused by Entamoeba histolytic. E. histolytic can affect the intestine, liver, kidney, brain and spleen. Amoebiasis inside the intestine is called intestinal amoebiasis, Amoebiasis in the visceral organs other than the intestine is called extra-intestinal amoebiasis. Amoebiasis in the liver is called hepatic amoebiasis. Amoebiasis in systemic organs other than the liver is called extrahepatic amoebiasis.

Symptoms of amoebiasis may vary from no symptoms (Asymptomatic amoebiasis) to mild amoebic diarrhoea to fulminating amoebic dysentery with mucus and blood in the stool.  Patients suffering from asymptomatic amoebiasis are carriers of E. histolytic and can spread the infection to others.

Both Protozoal cells and human cells are eukaryotic. Thus, Antirotzoal drugs have similar toxicity to both protozoal cells and human cells. It is difficult to treat protozoal infections.

The Life Cycle of E. histolytic:

E. histolytic exists as trophozoites and cysts. Amoeba cysts can survive inside the human body, outside the human body and in unfavourable conditions for a longer duration. These cysts are metabolically inactive E. histolytic cells. Trophozoites are metabolically active E. histolytic cells. They are invasive in nature and cannot survive outside the human body. Amoeba cyst enters the human body through food and water contaminated with amoeba cysts. Faecal matter containing E. histolytic contaminates food and water.

E. histolytic cysts can also enter the human digestive system through contaminated hands. Cyst becomes active inside the intestine and form trophozoites. These trophozoites are metabolically active and multiply inside the intestine, invade the mucosa of the large intestine and produce ulceration in the large intestine mucosal wall. Trophozoites from the colon may enter into the systemic circulation to produce systemic amoebic infection. Trophozoites slowly enter the rectum. Inside the rectum, these trophozoites form cysts and these cysts are excreted out from the body with faecal matter.

Classification of antiamoebic drugs

Antiamoebic drugs are classified on the basis of their site of action,

1. Luminal amoebicides: Diloxanide furoate, iodoquinpline, clioquinol, iodochlorohydroxyquinine, diiodohydroxyquinine, antibiotics like tetracycline, paramomycin, cifamide, etofamide.

2. Systemic and tissue amoebicides: emetine, chloroquine, dihydoemetine

3. Mixed amoebicides: metronidazole, tinidazole, ornidozole. secnidazole.

Luminal amoebicides: These are effective against E. histolytic trophozoites present in the intestine, rectum and colon. They are ineffective against trophozoites present inside the tissue of the GIT wall or inside systemic organs. These drugs are used to treat asymptomatic amoebiasis or mild condition of intestinal amoebiasis. Usually, they are recommended in combination with mixed amoebicides or systemic amoebicides.

Systemic or tissue amoebicides: Systemic amoebicides are effective against E. histolytic trophozoites present in the tissue of the intestinal wall, rectal wall, colon wall or inside systemic organ cells. They are not effective against trophozoites present in the GIT lumen. Thus these drugs are not effective for the complete cure of amoebiasis. These drugs should be administered with luminal amoebicides or mixed amoebicides for a complete cure of amoebiasis disease.

Mixed amoebicides: Mixed amoebicides are effective against all types of amoebiasis like intestinal amoebiasis and systemic amoebiasis, (invasive amoebiasis).

MIXED AMOEBICIDES:

1. Metronidazole:

   It is the prototype of mixed amoebicides. It produces a killing effect against various protozoa and anaerobic bacteria. Metronidazole is rapidly and almost completely absorbed from GIT. However, some metronidazole remains unabsorbed that enter the rectum and colon. It is well distributed throughout the body. It is metabolised in the liver by oxidation by the enzyme mixed-function oxidase followed by glucuronidation. Metabolites are excreted in urine, saliva. etc.

   Mechanism of action: Metronidazole is toxic to anaerobic microorganisms, amoeba and hypoxic cells. These cells have ferredoxin. Ferredoxin causes a reduction of metronidazole to produce highly reactive radicals. These radicals are cytotoxic and cause breakage in the DNA strand. Aerobic condition decreases the potency of metronidazole.

   Therapeutic uses: (Indications)  To treat asymptomatic amoebiasis, amoebic dysentery, hepatic amoebiasis and amoeboma.

   • It is not much effective to control asymptomatic amoebiasis because it is rapidly and almost completely absorbed from GIT.

   • It is very much effective in the treatment of amoebic dysentery.

   • Metronidazole concentration in the liver is very high. Thus it is effective in the treatment of hepatic amoebiasis. In severe conditions, metronidazole is administered through an intravenous route.

   • Metronidazole is effective in the treatment of hepatic abscesses, pulmonary abscesses, brain abscesses and renal abscesses due to E. histolytic. In these conditions, the intravenous route for Metronidazole administration is preferred. These diseases are called amoeboama.

   Side effects:

   • CNS: CNS side effects are rare but it may develop into serious conditions like seizures, numbness, and paresthesia. Some less serious conditions like dizziness, vertigo, insomnia, headache, weakness and depression may develop.

   • GIT: Nausea and anorexia, which may lead to headaches. Some common side effects are vomiting, diarrhoea, epigastric distress, and abdominal pain. Metronidazole is excreted in saliva that may cause metallic taste development, furry tongue and glossitis.

   • Urticaria, Dryness in mouth, fever and hypersensitivity reactions.

   • Reversible leukopenia: Intravenous administration develops thrombophlebitis Deep red-brown colour urine, Dysuria, crystal uria, cystitis, polyuria,

     WHO has declared metronidazole a carcinogenic agent.

     Drug interaction:

     • Metronidazole with alcohol produces a disulfiram-like reaction. Nausea, vomiting, flushing tachycardia, and dyspnea.

     • During metronidazole therapy, alcoholic beverages should be avoided.

     • Metronidazole potentiates the warfarin effect that prolongs blood clotting time

     • Drugs that promote the hepatic secretion of microsomal oxidase enzymes decrease the half-life of metronidazole. Examples are phenobarbitol, phenytoin,

     • Drugs that reduce or inhibit hepatic secretion of microsomal oxidase enzyme increase the duration of action of metronidazole. Examples are cimetidine.

     Contraindication:

     Metronidazole is contraindicated during pregnancy due to its teratogenic, carcinogenic and mutagenic effects. Metronidazole should not be administered to lactating women as metronidazole is excreted in breast milk.

     Dose: The recommended dose is 500 mg orally two times a day for 7 to 10 days.

LUMINAL AMOEBICIDES

1. Diloxanide furoate:

   It is recommended in asymptomatic intestinal amoebiasis that excretes E. histolytic cyst in faeces. It is administered orally. That is rapidly absorbed from GIT. It undergoes hydrolysis in the intestinal mucosal wall. 90% of the drug is absorbed from GIT into the systemic circulation. Rest remains in the Intestine that acts as luminal amoebicides. It is metabolised in the liver by glucuronidation. Glucuronide metabolites are excreted in the urine.

   Contraindications: Diloxanide furoate is a safer drug. But it is contraindicated under the following conditions:

   • Hypersensitive patient to diloxanide furoate.

   • Pregnancy and breastfeeding,

   • Liver impairment, Diloxanide furoate is not metabolised in liver disease. This may produce a toxic effect.

   • Children under 3 years/

   Dose: 500 mg three times a day orally for 10 days.

2. Paromomycin:

   It is an antibiotic. It has both bactericidal and amoebicidal effects and is also effective against tapeworms. It is poorly absorbed from GIT thus it produces its effect in the GIT lumen. However, it is not preferred due to the availability of a more effective luminal amoebisidal drug. It produces mild side effects in GIT such as nausea, diarrhoea, GIT disturbance, and abdominal cramp. It may also cause irreversible ototoxicity and nephrotoxicity. Superinfection is also reported that is an overgrowth of bacteria and fungus upon prolonged use of Paromomycine.

   Mechanism of action: Inside GIT it produces an amoebicidal effect as well as reduces bacterial flora population. Amoeba is a parasite and lives on intestinal bacterial flora. A decrease in the bacterial population will reduce the survival of amoeba inside GIT. Paromomycin develops leakage from microbial cell walls that causes the death of microbes.

   Other antibiotics like norfloxacin and tetracycline are recommended in luminal amoebiasis but they do not cause direct amoebicidal effect. They produce an antiamoebic effect by decreasing the population of bacteria present in the intestine.

   Contraindications: 

   • Hypersensitivity,

   • Pregnancy and breastfeeding,

   • Renal impairment

   • Children under the age of 5 years,

   • Coadministration with ototoxic drugs.

   Dose: 500 to 1000 mg three times a day for 5 to 10 days

3. Halogenated hydroxyquinoline:

   Diiodohydroxyquine and iodochlorohydroxyquine are used as luminal amoebicides. They are effective against E histolytic trophozoites in the intestinal lumen. But they are not effective against trophozoites present in liver or intestinal wall tissue. They are recommended for mild intestinal amoebiasis or asymptomatic amoebiasis. They are also used as a prophylactic agent to prevent hepatic amoebiasis. Common side effects are nausea, vomiting, diarrhoea, abdominal cramp, pruritis, and headache. Iodine taxidermy and thyroid gland enlargement may also occur. Dose and duration of treatment varies depending upon severity of infection.

   Contraindications:

   • Hypersensitivity,

   • Pregnancy and breastfeeding,

   • Renal impairment

   • Children under the age of 5 years,

   • Kidney and liver disease.

   • Blood disorders

SYSTEMIC AMOEBICIDES

Chloroquine: Chloroquine is a systemic amoebicide. It is rapidly absorbed from GIT. Thus it cannot produce a luminal effect. Its maximum concentration is in the liver after absorption from GIT. Thus it is highly effective to eliminate E histolytic trophozoites from the liver both in hepatic amoebiasis as well as in an amoebic liver abscess. It is recommended with metronidazole and diloxanide furoate in the treatment of hepatic amoebiasis or in the prevention of hepatic amoebiasis or hepatic abscess. If metronidazole is ineffective, chloroquine is recommended with emetine or dihydro-emetine. Luminal amoebicide must be recommended with chloroquine for a complete cure of amoebiasis. It is contraindicated in hypersensitivity, ratinopathy, Porphyria, liver or kidney disease, children under 6 months of the age 600 mg one time daily for two days followed by 300 mg once daily for two weaks.Dose: 

Emetine and dihydroxy emetine: Emetine and dihydroxy emetine are very toxic drugs. They have been completely replaced by nitroimidazole derivatives in the treatment of amoebiasis. They are used as an alternate drug if nitroimidazoles are not effective. However, dihydroxyacetone is less toxic than emetine. These drugs are administered through intravenous injection. They mainly concentrate on the liver and kidneys. They are very slowly metabolised and excreted. Emetine remains in the liver at least for 1 month and its half-life is about 5 days. Dose 1 mg/kg body weight not more than 60 mg daily for three days. 

They act as amoebicidal in the liver but are not effective against amoeba in the intestinal lumen. They inhibit protein synthesis in E histolytic trophozoites leading to the death of trophozoite cells.

Side effects: Nausea, vomiting and diarrhoea. Cardiac toxicity like arrhythmia hypotension CHF, tachycardia, cardiac dilation dyspnea, skeletal muscle weakness, skeletal stiffness, urticaria and pruritis, and rashes at the site of injection.