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D.VIJAY KUMAR09DG1R0013

T.K.R.COLLEGE OF PHARMACY

Presented by

WHAT IS CHEMOTHERAPY

Chemotherapy can be defined as the use of chemicals in infectious diseases to destroy microorganisms without damaging the host tissues

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The chemical agent should be toxic to pathogenic micro organism and minimal effect on host cell. The selective toxicity is important for these drugs.

Basic principle of chemotherapy

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BIOCHEMICAL REACTIONS OF ALL BACTERIAL CELLS

Class 1:- Energy productionClass2:- Growth and servival Class3:- Replication

These reactions are potential targets for attack by antibacterial drugs.

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Class 1 : These reactions are poor targets , for two reasons .

First ,there is no difference between bacteria and humans cells in the mechanism for obtaining energy from glucose .

second , even though selective toxic to ATP synthesis in the bacteria. It could be used alternative sources like lactate and amino acids .

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BIOCHEMICAL REACTIONS AS POTENTIAL TARGETS

Class 2 : These reactions are good targets because folic acid bio synthesis pathway takes place only in bacteria not in human cells. But folic acid is required in the synthesis of nucleic acid in both human cells and bacterial cells.

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PABA sulfonamide Dihydropterate synthetase

DHFA Trimethoprim Dihydrofolate reductase

THFA 5-flurouracil Thymidylate

synthetase

THYMIDYLATES DNA

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FOLIC ACID SYNTHESIS

class 3 : These reactions are particularly best targets for selective toxicity.

There are very distinct differences between mammalian cells and parasitic cells.

That are : The synthesis of peptidoglycan Protein synthesis Nucleic acid synthesis

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What is Leprosy

Leprosy, also known as Hansen's disease (HD), is a chronic disease caused by the bacteria Mycobacterium leprae

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Signs and symptoms

Neuropathic pain Skin lesions are the primary external

sign.  It causing permanent damage to the

skin, nerves, limbs, and eyes. Collapsed nose.

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Depending on clinical features, leprosy is classified as:

Indeterminate leprosy (IL) Tuberculoid leprosy (TT) Borderline tuberculoid leprosy (BT) Lepromatous leprosy (LL)

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Stages of leprosy:

1st stage: bacteria 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.

TREATMENT

Pre-modern treatment : Chaulmoogra oil

Modern treatment : Dapsone Rifampicin Clofazimine

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Chaulmoogra oil

A common pre-modern treatment of leprosy was chaulmoogra oil.

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 BurmaBurma

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DAPSONE

Dapsone (diamino-diphenyl sulfone) is an antibacterial most commonly used in combination with  rifampicin  and  clofazimine as multidrug therapy (MDT) for the treatment of Mycobacterium leprae infections leprosy

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SYNTHESIS OF DAPSONE:

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4,4-Dinitrodiphenyl sulfide sulfoneDapsone

MECHANISM OF ACTION

Dapsone is chemically related to the sulfonamides.

It acts by inhibition of folic acid synthesis

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PABA DAPSONE Dihydropterate

synthetase

DHFA Dihydrofolate

reductase

THFA Thymidylate

synthetase

THYMIDYLATES DNA

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PHARMACOKINETICS :

Dapsone is given orally and is well absorbed and widely distributed through body water and all tissues.

The plasma half-life is 24-48hrs. It is metabolised in the liver and

excreted through urine.

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Unwanted effects :

Methaemoglobinaemia Hepatotoxicity Photo sensitivity Haemolytic anaemia Nausea and vomiting.

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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, bacteria develops resistance .

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Mechanism of action:

Rifampicin inhibits bacterial DNA-dependent RNA synthesis by inhibiting bacterial DNA-dependent  RNA polymerase   RNA polymerase enzyme.enzyme.

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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.

Plasma half-life is 1-5 hrs. , Though urinary elimination accounts

for only about 30% of the drug excretion. About 60% to 65% is excreted through the feces.

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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.

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CLOFAZIMINE:

Clofazimine is a fat-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

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Systematic (IUPAC) nameN,5-bis(4-chlorophenyl)-3-(propan-2-ylimino)-3,5-dihydrophenazin-2-amine

CLOFAZIMINE:

Mechanism of action:

Clofazimine works by binding to the guanine bases of bacterial DNA, thereby blocking the template function of the DNA and inhibiting bacterial proliferation.

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Pharmacokinetics:

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.

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Unwanted effects:

Reddish colour of urine. Clofazimine produces pink to

brownish skin pigmentation in 75-100% of patients within a few weeks, as well as similar discoloration of most body fluids and secretions.

These discolorations are reversible but may take months to years to disappear.

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H.P.RANG & M.M. DALE, TEXT BOOK OF PHARMACOLOGY,5th EDITION ,PG NO: 620-653

K.D.TRIPATHI,TEXT BOOK OF PHARMACOLOGY,PG NO:335-41

R.S.SATOSKAR, PHARMACOLOGY AND PHARMACOTHERAPEUTICS,21ST EDITION,PG NO:755-59

SALIL K BHATTACHARYA, PARANTAPA SEN, ARUNABHA RAY, PHARMACOLOGY,SECOND EDITION,PG NO:413-416

Padmaja Udaykumar,, textbook of Medical Pharmacology,

Second Edition, Pg no:337-343

http://www.Uic.edu/pharmacy

http://www.Suite101.com

http://www.aac.asm.org http://www.pathmicro.med.sc.edu

http://www.quizlet.com

http://www.merckmanuals.com

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