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.

AntiLeprotic Drugs

• Leprosy is an infectious disease caused by a acid fast bacillus called as “Mycobacterium leprae”.
• Leprosy is called as “Kushtharog or Maharog” in India.
• This disease is present from ancient times but,the Gregor Hansen in 1873 discovered the causative organism as “Mycobacterium leprae” hence the disease is called as “Hansen’s Disease” also.
• The leprosy bacillus attacks the schwan cell nucleus in neuron and hence affects the peripheral nervous system and skin.     

Signs of Leprosy:

• Leprosy is characterized by presence of patches on skin, the patches of leprosy are characterized  by,

1. Definite loss of sensation.
2. Do not itch or hurt.
3. hypopigmentation to reddish or copper red colored.
4. No sensation of pain.
5. May be flat or elevated.

Diagnosis of Leprosy:

1. Leprosy patches can easily be identified by checking sensation in comparison to normal skin.
2. Skin smear test for presence of bacterias.

Mycobacterium leprae:

• Its a acid fast bacillus and shows positive reaction to Zeil-Nellson Reagent test.
• This bacteria grows very slowly : Has incubation period of 5 yrs.
• This is the first bacteria discovered which is known to cause disease in humans.
• This bacterium was discovered by Gerhard Armauer Hansen in 1873.
• This bacteria can not be grown on artificial mediums, it has to be grown on certain lab animals like some species of monkeys, rats, armadillo and rabbits.
• Like Mycobacterium tubercles this bacteria is also known to produce resistance.

The drugs which are used in treatment of leprosy are called as “Antileprotic Drugs”

Classification:

1) Sulfones:

• Dapsone.
• Solapsone.
• Acedapsone.

2) Phenazines:

• Clofazimine.

3) Thiosemicarbazones:

• Amithiazone.

4) Antitubercular drugs:

• Rifampicin.
• Pyrazinamide.
• Ethionamide.

5) Antibiotics:

• Minocycline.
• Ofloxacin.
• Clarithromycin.

6) Natural:

• Chaulmoogra oil.

Dapsone

• Sulfones were first employed in treatment of leprosy in 1941, Dapsone is most favorable drug in the treatment of leprosy.
• 
• Chemical name : 4-4 Diamino Diphenyl Sulfone.

Mechanism of Action:

• Dapsone is a bacteriostatic and acts by inhibiting folic acid synthesis of mycobacterium.
• It has similar mechanism like sulfonamides i.e. it inhibits bacterial folate synthtase and prevent formation of dihydrofolic acid from PABA.
• It also has significant anti-inflammatory action.

Structure Activity Relationship: SAR:

1. Sulfone group is found essential for action as replacing it diminishes the activity.
2. Replacement of benzene rings with thiazole rings produced “Thiazosulfone” which is found to be less active as compared to Dapsone.
3. Replacement of one hydrogen from each amino group with acetyl group gave less active “Acedapsone” which is have less solubility and hence used for depot injections.
4. Replacement of one hydrogen from each amino group with –CH2SO2, gave rise to Sulfomethonates, which are having lesser activity.

     5. Solapsone was one of the Sulfomethonates having relatively lesser gastric irritation as compared to   Dapsone, and hence used in patients those who can not tolerate Dapsone.

Adverse Effects / Side Effects of Dapsone:

1. Gastric Irritation.
2. Dermatitis.
3. Anorexia.
4. hepatitis.
5. Psychosis.

Therapeutic Uses:

1. In treatment of multibacillary  (more than 5 patches) and paucibacillary (1 to 5 patches) leprosy in combination with other drugs.
2. In combination with Pyrimethamine, Dapsone is used in prophylaxis of malaria.
3. In certain inflammatory skin conditions like Polycondritis, leishminiasis etc.
4. To treat pneumonia in AIDS with Trimethoprim

Clofazimine.

• It is a secondary drug that is used in combination with other drugs used in treatment of Leprosy.
• Chemically its a “Phenazine” derivative.
• its is water soluble red dye known to cause discoloration of skin (Hypopigmentation.), sweat, sputum, feces, eye lid lining, urine etc.

Mechanism of Action:

• The exact mechanism through which Clofazimine exerts its effect is unknown.
• However, it binds preferentially to mycobacterial DNA, thereby inhibiting DNA replication and cell growth.
• Clofazimine has a slow bactericidal effect on Mycobacterium leprae and is active against various other Mycobacteria.
• It is also known to enhance the cellular defense system.

Structure Activity Relationship:

1. The “Phenazine” nucleus is found essential for Antimycobacterial and Immunosuppressive actions of Clofazimine.
2. The halogen substitution at para position of phenyl groups at C3 and N10 found to increase the activity.
3. The substitution at “imino” group is found to be essential as the substitution with alkyl and cycloalkyl groups increased the activity.

Adverse Effects / Side Effects:

1. GI irritation.
2. Change in color of skin.
3. Darkening of body secretions.
4. Scaly itchy skin.

Therapeutic Uses:

1. It is a secondary drug used in treatment of leprosy in combination with other drugs.
2. Its immunosuppressive action can be useful in treatment of many autoimmune diseases like sclerosis, psoriasis, type 1 diabetes etc.