AntiAmoebic Drugs

• Amoebiasis also called as Amoebic dysentery is an intestinal infection caused due to a protozoa called as “Entamoeba histolytica” and is characterized by dysentery associated with presence of blood and mucus in feces.
• This can be chronic or acute with patients showing varying degree of illness from no symptoms to mild dysentery to severe dysentery causing collapse and even death of the patient.
• Diagnosis is can be done by stool testing for presence of Entamoeba histolytica.
• Treatment is aimed not only for the patients with symptoms but also for the one those who are dormant carriers of the disease.
• The drugs which are used in treatment of the Amoebiasis are called as “Antiamoebic Drugs”

Life cycle of Entamoeba histolytica:

• Entamoeba histolytica exist in two life forms,

1. Cysts: (Tough form, non-motile and can exist outside the body).
2. Trophozoites: (Motile form, can not exist outside the body).

• Life cycle consists of following steps:

1. Entry of cysts in the body:

• Cysts enter into the body through contaminated food, contaminated water or through feces.

2. Formation of Trophozoites:

• Cysts after entering into the intestinal lumen gets converted into the motile Trophozoites.
• Trophozoites penetrates the intestinal wall and starts multiplying in colon cells often resulting in rupture of the colon cells causing local bleeding and hence triggering dysentery (blood itself is purgative).
• Sometimes trophozoites never invade the local colon cells instead they feed only on intestinal bacterial flora can may cause mild diarrhea.

3.  Invasion into Systemic Circulation:

• Large concentrations of intestinal trophozoites leads to systemic invasion of trophozoites resulting into entry of trophozoites into other tissues like liver, lungs and even brain also.

4. Formation of Cysts:

• Trophozoites in intestine are slowly moved towards rectum where they gets converted into cysts and are discarded into the feces.
• And cycle continues.

Classification of Antiamoebic Drugs:

A. Tissue Amoebicides:

a) For both intestinal and extra intestinal form of Amoebiasis:
I) Nitroimidazoles:

1. Metronidazole (Metrogyl)
2. Tinidazole (Flagyl)
3. Ornidazole (Orni)
4. Secnidazole.
5. Satranidaole

II) Alkaloids:

1. Emetine.
2. Dehydroemetine.

b) For extra intestinal amoebiasis:

1. Chloroquin (Lariago)

B) Luminal Amoebicides:
a) Amides:

1. Diloxanide furoate.
2. Nitazoxznide.

b) 8- Hydroxyquinolines:

1. Quinidochlor.
2. Iodoquinol.

c) Antibiotics:

1. Tetracyclines.

Metronidazole

• Its a Nitroimidazole derivative used as Antiamoebic as well as an antibacterial drug.
• Its a prodrug and required get converted into its active form when reaches inside the microorganism.
• IUPAC Name: 2-(2-methyl-5-nitroimidazol-1-yl)ethanol.

Structure Activity Relationship:

1. The 5-nitroimidazole ring with 3-methyl is essential for action.
2. Substitution at N-1 with alkyl derivatives produced more active compounds like, Tinidazole, Ornidazole and Secnidazole.
3. Tinidazole: 1-(2-ethylsulfonylethyl)-2-methyl-5-nitroimidazole
4. Ornidazole: 1-chloro-3-(2-methyl-5-nitroimidazol-1-yl)propan-2-ol
5. Secnidazole: 1-(2-methyl-5-nitroimidazol-1-yl)propan-2-ol

Mechanism of Action:

• After reaching the bacterial cell metronidazole is get reduced by “Electron Transport Chain” proteins of micro-organism like Ferridoxin.
• The Reduced form of Metronidazole is highly reactive and combines with bacterial DNA strand and breaks it down.
• Hence Metronidazole is supposed to act by destructing bacterial DNA strand, stopping its protein synthesis.

Adverse Effects / Side Effects:

1. Nausea.
2. Anorexia.
3. Vomiting.
4. Epigastric Distress.
5. Thrombocytopenia.

Therapeutic Uses:

1. Drug of Choice In treatment of Amoebiasis.
2. In treatment of Giardiasis.
3. In treatment of Trichomoniasis.
4. In treatment of various mixed infections.
5. In anaerobic infections.
6. In treatment H. pylori infection along with antibiotics and PPI (Proton Pump Inhibitors).
7. In treatment of Acne rosea.

Doses:

1. Acute Intestinal amoebiasis: 800mg TDS for 10 days with luminal amoebicide.
2. Mild Intestinal amoebiasis: 400mg TDS for 5-7 days.
3. Hepatic Amoebiasis: 1G IV followed by 0.5 G IV every 8hrs for 10 days.

Emetine

• Its an Isoquinoline alkaloid obtained from roots of the plant “Cephalis ipecacuanha” belonging to family “Rubiaceae”.
• It has derived its name from its powerful emetic action and is a fast acting emetic.
• It is also a powerful amoebicide but is now reserved due to its side effect profile.
• IUPAC Name: (2S,3R,11bS)-2-[[(1R)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl]methyl]-3-ethyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-benzo[a]quinolizine.

Mechanism of Action:

• Emetine inhibits protein synthesis in eukaryotic (but not prokaryotic) cells by irreversibly blocking ribosome movement along the mRNA strand and inhibits DNA replication in the early S phase of the cell cycle.

Adverse Effects/ Side Effects:

1. Nausea.
2. Anorexia.
3. Vomiting.
4. Skeletal and cardia myopathies.

Diloxanide Fuorate:

• Diloxanide furoate is a prodrug which releases active drug “Diloxanide” in intestinal lumen.
• It is classified as luminal amoebicide.
• IUPAC NAME: [4-[(2,2-dichloroacetyl)-methylamino]phenyl] furan-2-carboxylate.

Mechanism of Action:

• Its exact mechanism of action is not known however, as it has structural similarity with “Chloramphenicol” it is supposed to act by inhibiting protein synthesis of the amoeba.

Adverse Effects / Side Effects:

1. Nausea.
2. Anorexia.
3. Vomiting.
4. Flatulence.

Idoquinol

• Its a 8-Hydroxy Quinoline derivative.
• It is poorly absorbed from GIT and largely remains in intestinal lumen.
• It acts by chelation of Ferrous ions essential for amoeba’s metabolism.
• It is considered as drug of choice for asymptomatic amoebiasis.
  
• IUPAC Name: 5,7-diiodoquinolin-8-ol.
• It is well tolerated only complication is gastric cramps.
• Its other sister compound having same activity potential is Cleoquinol.

• IUPAC Name: 5-chloro-7-iodoquinolin-8-ol.