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.