0% found this document useful (0 votes)
26 views10 pages

2022_Unit_2(B)_Leprosy Notes_JPRaval_MSc_Pages_1_10

Uploaded by

prabhakar.7567
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
Available Formats
Download as PDF, TXT or read online on Scribd
0% found this document useful (0 votes)
26 views10 pages

2022_Unit_2(B)_Leprosy Notes_JPRaval_MSc_Pages_1_10

Uploaded by

prabhakar.7567
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
Available Formats
Download as PDF, TXT or read online on Scribd
You are on page 1/ 10

M.Sc.

Organic Chemistry (Semester – IV)


Paper – 4 : Medicinal Chemistry

UNIT – II: (B) Anti – Mycobacterial


ycobacterial agents

Dr. Jignesh P. Raval


Principal,
The Mandvi Education Society Science College,
Mandvi

----------------------------------------------------------------------------------------------------
NOTE
Disclaimer
This study material is prepared by Dr. Jignesh P. Raval; The basic objective of this
material is to supplement teaching and discussion in the classroom in the subject.
Students are required to go for extra reading in the subject through library work.
Antimycobacterials: AntiLeprotic agents…………………………………………….Dr. Jignesh P.Raval

Antimycobacterials: AntiLeprotic agents


Chemotherapy of Tuberculosis & Leprosy (Antimycobacterials)

Introduction:
 Antitubercular drugs- used to treat tuberculosis (TB), caused by Mycobacterium
tuberculosis.
 Antileprotic drugs- used to treat leprosy, caused by Mycobacterium leprae.
Mycobacteria are intrinsically resistant to most antibiotics due to following characteristics:

1. They grow slowly compared with other bacteria; antibiotics that are most active against
growing cells are relatively ineffective.
2. Mycobacterial cells can also be dormant and thus completely resistant to many drugs or
killed only very slowly by the few drugs that are active.
3. Lipid-rich mycobacterial cell wall is impermeable to many agents.
4. Mycobacterial species are intracellular pathogens, and organisms residing within
macrophages are inaccessible to drugs that penetrate these cellspoorly.
5. Finally, mycobacteria are notorious for their ability to develop resistance.
Combinations of two or more drugs are required to overcome these obstacles and to prevent
emergence of resistance during the course of therapy. The response of mycobacterial infections
to chemotherapy is slow, and treatment must be administered for months to years, depending
on which drugs are used.

Leprosy
Alternative Name of Leprosy: Hansen's disease

 Leprosy is an infectious disease derived from the French work "leper" and from the Greek
word "lepros" which means scaly, referring to the scales that form on the skin in some
cases of leprosy and that has been known since biblical times.
 Leprosy is characterized by disfiguring skin sores, nerve damage, and progressive
debilitation.
 Leprosy is caused by a bacterium which affects various parts of the body, including in
particular the skin and nerves.
 Leprosy is a difficult disease to transmit and has a long incubation period.
 Children are more susceptible than adults to contracting the disease.

Complications of Leprosy : Leprosy can cause:


1. Cosmetic Disfigurement
2. Muscle Weakness
3. Nerve Damage in the Extremities
4. Sensory Loss in the Skin
5. Long-term leprosy may lose the use of hands or feet due to repeated injury resulting
from lack of sensation.

Causes of Leprosy
 Leprosy is caused by the organism : Mycobacterium leprae:
 Mycobacterium leprae grow slowly and mainly affect the skin, nerves, and mucous
membranes. Children are more susceptible than adults to contracting the disease.

MSc Organic Chemistry Semester – IV 1 | Page


Antimycobacterials: AntiLeprotic agents…………………………………………….Dr. Jignesh P.Raval

 Person to Person: Most scientists believe that leprosy spreads from person to person
through infected respiratory droplets. While this is one mode of leprosy transmission.

People who are at the greatest risk of leprosy transmission are:


1. Parents of someone with leprosy
2. Children of someone with leprosy
3. Brothers or sisters of someone with leprosy.
4. The extent of exposure
5. Genetics
6. Environmental conditions
Leprosy is common in many countries worldwide, and in temperate, tropical, and subtropical
climates. Effective medications exist, and isolation of victims in leper colonies is unnecessary.

Signs & Symptoms of Leprosy


Leprosy symptoms generally appear three to five years after a person becomes infected with the
bacteria that cause the disease. However, it can take as short as a few months or several
decades. Leprosy symptoms include:
1. Eye Problems
2. Muscle Weakness
3. Skin Rash
4. Skin Stiffness
5. Skin lesions that are lighter than your normal skin color
6. Lesions have decreased sensation to touch, heat, or pain
7. Lesions do not heal after several weeks to months
8. Numbness or absent sensation in the hands, arms, feet, and legs
9. It is important to note that not all leprosy patients lose their fingers and toes. With early
diagnosis and leprosy treatment, many of these symptoms can be prevented.

Stages of leprosy:
 1st stage: A bacterium enters through skin, the skin sensation become dull and small
patches develop. In this stage the bacteria multiply in the axoplasm of nerve fibers
causing tingling sensations.
 2nd stage: skin becomes thick and wrinkled, ears become swollen, nodules are formed in
skin of nose and throat. These nodules discharge fluid which is highly infectious.
 3rd stage: the bacteria burst out of the nerve cell and go to peripheral tissues and begin
to proliferarate. This results in deformities in hands, feet, face and toes etc.

Classification

Types of Leprosy
There are two main types of leprosy:
1. Tuberculoid (Paucibacillary leprosy)
2. Lepromatous ((Multibacillary Hansen’s disease))
Both types of leprosy produce lesions on the skin, but the latter form i.e. Lepromatous is most
severe which produces large disfiguring nodules.

 This chronic infectious disease usually affects the skin and peripheral nerves but has a
wide range of possible clinical manifestations.
 Patients are classified as having paucibacillary or multibacillary Hansen's disease.
 Paucibacillary Hansen's disease is milder and characterized by one or more
hypopigmented skin macules.

MSc Organic Chemistry Semester – IV 2 | Page


Antimycobacterials: AntiLeprotic agents…………………………………………….Dr. Jignesh P.Raval

 Multibacillary Hansen's disease is associated with symmetric skin lesions, nodules,


plaques, thickened dermis, and frequent involvement of the nasal mucosa resulting in
nasal congestion and epistaxis.
Depending on clinical features, leprosy is classified as or The forms of leprosy are based
on the person‘s immune response to M. Leprae.
1. Indeterminate leprosy (IL)
2. Tuberculoid leprosy (TT)
3. Borderline tuberculoid leprosy (BT)
4. Borderline lepromatous leprosy
5. Mid-borderline leprosy
6. Lepromatous leprosy (LL)
 Indeterminate leprosy: A few hypopigmented macules; can heal spontaneously,
persists or advances to other forms.
 Tuberculoid leprosy: A few hypopigmented macules, some are large and some become
anesthetic (lose pain sensation) some neural involvement in which nerves become
enlarged; spontaneous resolution in a few years, persists or advances to other forms.
 Borderline tuberculoid leprosy: Lesions like tuberculoid leprosy but smaller and
more numerous with less nerve enlargement; this form may persist, revert to
tuberculoid leprosy, or advance to other forms.
 Borderline lepromatous leprosy: Many skin lesions with macules (flat lesions)
papules (raised bumps), plaques, and nodules, sometimes with or without anesthesia;
theform may persist, regress or progress to lepromatous leprosy.
 Mid-borderline leprosy: Many reddish plaques that are asymmetrically
distributed,moderately anesthetic, with regional adenopathy (swollen lymph nodes);
the form may persist, regress to another form, or progress.
 Lepromatous leprosy: Early lesions are pale macules (flat areas) that are diffuse and
symmetric; later many M. leprae organisms can be found in them. Alopecia (hair loss)
occurs; often patients have no eyebrows or eyelashes. As the disease progresses, nerve
involvement leads to anesthetic areas and limb weakness; progression leads to aseptic
necrosis (tissue death from lack of blood to area), lepromas (skin nodules), and
disfigurement of many areas.

Transmission:
 Nasal droplet
 Infected soil
 Aerosolized M.Leprae
 Sneeze
 Direct dermal inoculation
 Leprosy can also be hereditary
 Routes of transmission are still being researched for leprosy

Prevention consists of:


1. Avoiding physical contact with untreated people
2. People who are in immediate contact with the leprosy patient should be tested for
leprosy.
3. Annual examinations should also be conducted on these people for a period of five years
following their last contact with an infectious patient
4. Reconstructive surgery is aimed at preventing and correcting deformities.
5. Comprehensive care involves teaching patients to care for themselves.

MSc Organic Chemistry Semester – IV 3 | Page


Antimycobacterials: AntiLeprotic agents…………………………………………….Dr. Jignesh P.Raval

6. Physiotherapy exercises are taught to the patients to maintain a range of movement in


finger joints and prevent the deformities from worsening.

MSc Organic Chemistry Semester – IV 4 | Page


Antimycobacterials: AntiLeprotic agents…………………………………………….Dr. Jignesh P.Raval

Treatments of Leprosy
1. Historically, there was no cure for leprosy. With early diagnosis and treatment of
leprosy the symptoms and complications can be minimized.
2. It is important to note that treatment of leprosy differs depending upon the form of the
disease. Treatment will generally continue for one year for tuberculoid leprosy and for
two years for lepromatous leprosy.
3. Treatment of leprosy typically involves medicines along with supportive care.
Supportive care is aimed at treating symptoms and associated complications. A number
of different antibiotics are used to kill the bacteria that cause the disease.
4. Aspirin, prednisone, or thalidomide are used to control inflammation.
5. Many times, medicine for treatment of leprosy can be provided at no cost to patients by
their family doctor or through the Hansen's Disease Clinic closest to them. A person
should see improvements after two to three months of beginning treatment.
6. Pre-modern treatment : Chaulmoogra oil
7. Modern treatment is use of : Dapsone;
Rifampicin
Clofazimine

Pharmacological Treatment:
 Multiple Drug Treatment (MDT)
There are several effective chemotherapeutic agents:
 Dapsone (diaphenylsulfone, DDS)
 Rifampicin (RFP)
 Clofazimine (CLF),
 Ofloxacin (OFLX)
 Minocycline (MINO) constitute the backbone of the multidrug therapy (MDT) regimen.

1. Chaulmoogra oil
 A common pre-modern treatment of leprosy was chaulmoogra oil.
 It contains glycerides of chaulmoogric acid and Hydnocarpic acid.
 The oil has long been used in India as an Ayurvedic medicine for the treatment of
leprosy and various skin conditions. It has also been used in China and Burma.
 A component of chaulmoogra oil found in seeds of the tree Hydnocarpus wightiana
(known as chaulmugra in Hindi and Persian), it has played a key role in the treatment of
leprosy since antiquity.

MSc Organic Chemistry Semester – IV 5 | Page


Antimycobacterials: AntiLeprotic agents…………………………………………….Dr. Jignesh P.Raval

2. Sulfones: Dapsone (diaphenylsulfone, DDS):


O

H 2N S NH2

O
DDS (Dapsone)
• Chemically – Sulfonamides i.e. sulfone
• Mode Of Action: It acts by inhibiting the folate synthesis

• Pharmacokinetic properties:
• Oral Tablets (Available in 25mg & 100 mg tablets);
• Half life (T ½) = 24-48 hrs
• It is metabolized in the liver and excreted through urine.

 Adverse Drug Reactions (ADRs):


• Anemia
• Anorexia, Allergic dermatitis
• Hepatotoxicity
• Photo sensitivity
• Haemolytic anaemia
• Nausea and vomiting.

c. Synthesis:
• Dapsone, (4,4-diaminodiphenylsulfone) (34.2.3), is synthesized from either 4-
chloronitrobenzene or from the sodium salt of 4-acetamidobenzenesulfonic acid.
• Reacting 4-chloronitrobenzene with sodium sulfide gives 4,4-dinitrodiphenylthioester
(34.2.1), and oxidation of the sulfur atom in this compound using potassium dichromate
in sulfuric acid gives 4,4-dinitrodiphenylsulfone (34.2.2). Reduction of the nitro group in
the resulting compound using tin dichloride in hydrochloric acid makes the desired
dapsone.

Anorexia: is an eating disorder characterized by immoderate food restriction and irrational fear of gaining weight, as
well as a distorted body self-perception. It typically involves excessive weight loss and is usually found more in
females than in males.
Anemia: is a decrease in number of red blood cells (RBCs) or less than the normal quantity of hemoglobin in the
blood.
Hemolytic anemia: is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells (RBCs), either
in the blood vessels (intravascular hemolysis) or elsewhere in the human body (extravascular).

MSc Organic Chemistry Semester – IV 6 | Page


Antimycobacterials: AntiLeprotic agents…………………………………………….Dr. Jignesh P.Raval

MSc Organic Chemistry Semester – IV 7 | Page


Antimycobacterials:: AntiLeprotic agents……………
agents…………………………………………….Dr.
…………………….Dr. Jignesh P.Raval

Rifampicin

 Rifampicin is rapidly bactericidal to Mycobacterium leprae .


 It can be conveniently given once a monthly.
 It is used in combination with dapsone in
multidrug therapy (MDT)
 Rifampicin given alone,
e, bacteria develops resistance.
resistance

Mechanism of action:
• Rifampicin inhibits bacterial DNA-dependent
DNA dependent RNA synthesis by inhibiting bacterial
DNA-dependent RNA polymerase enzyme.
Pharmacokinetics:
 Rifampicin is given orally and is widely distributed in the tissues and body fluids.
 Rifampicin is easily absorbed from the gastrointestinal tract because its ester functional
group is quickly hydrolyzed in the bile. (i.e. Enterohepatic cycling)
 Plasma half-life(T ½) is 1-5
5 hrs. ,
 Though urinary elimination accounts for only about 30% of the drug excretion. About 60% to
65% is excreted through the feces.

Unwanted effects:
 Orange colour of body fluids.
 Hepatotoxicity- liver failure in severe cases
 Respiratory problems- breathlessness
 Cutaneous - flushing, , rash, redness and watering of eyes.
 Abdominal - nausea, vomiting, abdominal cramps with or without diarrhoea.
 Flu-like symptoms - fever, headache.

Clofazimine
Generic Name: Clofazimine

 Clofazimine is a fat-soluble
soluble riminophenazine dye
 Used in combination with rifampicin and dapsone as
multidrug therapy (MDT) for the treatment of leprosy.
 It has been used investigationally in combination with other
antimycobacterial drugs to treat Mycobacterium – avium
infections in AIDS patients
 It is dye having Anti-inflammatory
inflammatory activity
Mode Of Action:
 Against Leprosy bacilli may involve action on DNA i.e. Clofazimine works by binding to
the guanine bases of bacterial DNA, thereby blocking the template function of the DNA
and inhibiting bacterial proliferation.
Pharmacokinetic properties:
 Oral; 6-7 weeks; Plasma Half Life ((T ½) is 8 weeks
 Clofazimine is given orally and is widely distributed in the tissues and body fluids.
 But clofazimine has a very long half life of about 70 days.
 It is metabolised in the liver and excreted through urine.
Uses:
• Clofazimine
imine exhibits a bactericidal effect between that of dapsone and rifampicin.
Adverse
dverse Drug Reactions(ADRs):
Reactions(ADRs)
 Reddish urination
 Blue – black discoloration of lesions

MSc Organic Chemistry Semester – IV 8 | Page


Antimycobacterials: AntiLeprotic agents…………………………………………….Dr. Jignesh P.Raval

 Nausea, Giddiness, headache, GI disturbances


Synthesis:

Clofazimine, (34.2.6), is synthesized by oxidizing 2-(p-chloroanilino)aniline using a solution of


iron (III) chloride in water, which leads to the formation of 2-(p-chloroanilino)-5-(p-
chlorophenyl)-3,5-dihydro-3-iminophenazine (34.2.5). Upon reacting this with a primary
amine, in particular isopropylamine, the hydrogen atom in the imine region of the molecule is
formally replaced with an alkyl group of the introduced amino group (in this case with an
isopropyl group), forming the desired drug—clofazimine.

MSc Organic Chemistry Semester – IV 9 | Page

You might also like