1. INTRODUCTION OF CHEMOTHERAPY

BYBY

Dr. Dr. SAMINATHAN KAYAROHANAMSAMINATHAN KAYAROHANAM

M.PHARM, M.B.A, PhDM.PHARM, M.B.A, PhD

INTRODUCTION OF INTRODUCTION OF CHEMOTHERAPYCHEMOTHERAPY

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NUM CONTENT SLIDE

I DEFINITIONS 4

II HISTORY 7

III MECHANISMS OF ANTIMICROBIAL AGENTS 9

IV MECHANISMS OF ANTIBACTERIAL RESISTANCE 17

V GENERAL PRINCIPLES OF ANTI-INFECTIVE THERAPY 28

VI IDEAL ANTIMICROBIAL DRUG 29

VII PREVENTION OF ANTIBIOTIC

RESISTANCE

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LEARNING OUTCOME

1. Able to understand and describe about antibiotics.

2. Understand the history of some antibiotics.

3. Abele to demonstrate the various mechanism of antibiotics.

4. Able to describe the antibiotic resistance mechanism and the types of resistance

5. Able to understand the principles of antibiotic therapy.

6. To gain the knowledge of ideal antimicrobial drug therapy.

7. Able to describe and demonstrate, how to prevent the antibiotic resistance.

Dr.K.Saminathan.M.Pharm, M.B.A, Ph.D

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I.DEFINITIONS

Chemotherapy is the drug treatment for the diseases caused by pathologic microorganisms, parasites, and tumour cells.

“Chemical substance used to kill the microorganism and cancer cell”

The objective of chemotherapy is to study and to apply the drugs that have highly selective toxicity to the pathogenic microorganisms and have no or less toxicity to the host.

CON ...4 Dr.K.Saminathan.M.Pharm, M.B.A, Ph.D

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WHAT IS AN ANTIBIOTIC?“Antibiotic” is from antibiosis, meaning against life.

“Substances produced by various species of microorganisms (bacteria, fungi, actinomycetes) to kill or suppress the growth of

other microorganisms”

The minimal inhibitory concentration (MIC)the minimum amount of a drug required to inhibit the growth of bacteria in vitro.

• The minimal bactericidal concentration (MBC)the minimum amount of a drug required to kill bacteria in vitro.

TYPENatural Antibiotics Antimicrobial drugs produced by microorganisms.

Synthetic Antibiotics Antimicrobial drugssynthesized in the lab. CON ...

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Antimicrobial spectrum : the scope thata drug kills or suppresses the growth ofmicroorganisms.

Narrow-spectrum: The drugs that only acton one kind or one strain of bacteria.(isoniazid )

Broad-spectrum: The drugs that have awide antimicrobial scope. (tetracycline,chloramphenicol )

CON ...


II.HISTORY

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1929 Penicillin discovered by Alexander FlemingMessy lab, cool damp weather, luck

1940 Florey and Chain mass produce penicillin for war time use, becomes available to the public.

1935 Sulfa drugs discovered1943 Streptomycin discoveredWestern civilization fundamentally changed

7Dr.K.Saminathan.M.Pharm, M.B.A, Ph.D

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III. MECHANISMS OF ANTIMICROBIAL AGENTS

1.INHIBITION OF CELL WALL SYNTHESIS

2.INHIBITION OF FUNCTIONS OF CELLULAR MEMBRANE

3. INHIBITION OF PROTEIN SYNTHESIS

4.INHIBITION OF NUCLEIC ACID SYNTHESIS

5.INHIBITION OF FOLIC ACID SYNTHESIS

CON ...

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BACTERIAL CELL STRUCTURE


10 1010 Dr.K.Saminathan.M.Pharm, M.B.A, Ph.D

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CON ...


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1. Inhibition of cell wall synthesis

– Penicillins and cephalosporins stop synthesisof wall by preventing cross linking ofpeptidoglycan units.

– Bacitracin and vancomycin also interferehere.

– Excellent selective toxicityCON ...


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2. Inhibition of functions of cellular membrane:

– The bacterial cell membrane is also calledcytoplasmic membrane. Its main compoundsare proteins and lipids.– Polymyxins can selectively combine withphosphatide in the cell membrane and causethe increase of membranous permeability. Asthe result, some important materials will outflow from bacterial cells and result in death of bacteria. CON ...


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3. Inhibition of protein synthesis– Due to differences in ribosomes

– Eucaryotic cells have 80S (60S + 40S subunits)ribosomes.

– Procaryotic cells have 70S (50S + 30S subunits)ribosomes.

– Examples:

• Chloramphenicol,Macrolides and Clindamycinbind to the 50S subunit.• Tetracyclines and Aminoglycosides bind tothe 30S subunit. CON ...


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4. Inhibition of nucleic acid synthesis

– Stop DNA replication

• Example: Quinolones-inhibiting DNAgyrase; Metronidazole???-DNAPolymerase

– Or stop RNA synthesis

• Example: Rifampin -binds to the bacterialDNA-dependent RNA polymerase.

CON ...


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5. Inhibition of folic acid synthesisA drug mimics a normal metabolite andacts as a competitive inhibitor.

– Enzyme of cell recognizes the drug instead ofthe normal metabolite-Pathway stops.– Example: Sulfonamides and trimethoprim are similar to PABA (para aminobenzoic acid).inhibit folic acid synthesis by blockingdihydrofolic acid synthase and reductaserespectively. CON ...


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IV.RESISTANCE TO ANTIBACTERIAL AGENTS

• Drug resistance is the phenomenon thatsusceptibility of pathogenic microorganismsto drugs becomes lower or even loses afterthe microorganisms contact with drugs manytimes.

• When the bacteria show resistance to onedrug, they are also resistant to some otherdrugs. This phenomenon is called crossdrug resistance. CON ...


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MECHANISMS OF ANTIBACTERIAL RESISTANCE

1.Inhibition of drug uptake or blocking the entry (Change their cell membrane and cellwall permeability to the drug)

2. Produce enzymes that destroy the chemical structures of drugs

3.Alter or modified the target molecule.

4. Activation of drug efflux pump.


RESISTANCE TO ANTIBIOTICS


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1. Mechanisms of antibacterial resistance Structurally modified antibiotic target site,resulting in:

– For example, as the receptor protein on the 30s ribosomal subunit may be deleted or altered as a result of mutation, some aminoglycosides cannot combine with the bacteria.

CON ...


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2. Mechanisms of antibacterial resistance

• Antibiotic inactivation– bacteria acquire genes encodingenzymes that inactivate antibiotics

• Examples include:– b-lactamases– aminoglycoside-modifying enzymes– chloramphenicol acetyl transferase CON ...


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3.Mechanisms of antibacterial resistance Develop an altered metabolic pathway– Bacteria can develop an altered metabolicpathway that bypasses the reaction inhibitedby drugs.– For example, sulfonamide resistance myoccur as a result of mutations that causeover-production of PABA or cause productionof a folic acid-synthesizing enzyme that haslow affinity for sulfonamides.Mechanisms of antibacterial resistancePABA, p-aminobenzoic acid


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4. Mechanisms of antibacterial resistance

Altered uptake of antibiotics, resulting in:– decreased permeability

– increased efflux

– For example, gram-negative bacillus caninduce some special proteins to block porinchannels in cell wall and prevent tetracyclines into the bacillus.

CON ...


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A) TRANSFERMATIONWhen naked DNA (Antibiotic-resistance Gene) is released on lysis of an organism and is taken up by another organism.

B) TRANSDUCTION Antibiotic-resistance genes are transferred from one bacterium to another by means of bacteriophages.

C) CONJUGATION Direct contact between two bacteria: Plasmids form a mating bridge across the bacteria and DNA is exchanged, which can result in acquisition of antibiotic-resistance genes by the recipient cell. Transposons can also carry antibiotic-resistance genes

GENETIC TRANSFER



COMMON ANTIMICROBIALS AND METHODS OF RESISTANCE

ANTIBIOTIC METHOD OF RESISTANCE

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Tetracycline

B-Lactams

Sulfonamides

Fluoroquinolones

Aminoglycosides

Active efflux from cell

Hydrolysis or protein binding

Overproduction of antibiotic target

Modification of antibiotics binding site

Enzymatic modification antimicrobial


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V. GENERAL PRINCIPLES OF ANTI-INFECTIVE THERAPY

Selection of an appropriate anti-infective agent

① Identification of the infecting organism shouldprecede antimicrobial therapy when possible.

② The pathogenic microorganism susceptibility toantimicrobial agents should be determined, if asuitable test exists.

③ Factors that influence the choice of an antiinfective agent or its dosage for a patientinclude the age, renal and hepatic function,pregnancy status, and the site of infection, etc.


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VI. IDEAL ANTIMICROBIAL DRUG

Have highly selective toxicity to the pathogenic

microorganisms in host body

Have no or less toxicity to the host.

Low propensity for development of resistance.

Not induce hypersensitive in the host.

Have rapid and extensive tissue distribution

Be free of interactions with other drugs.

Be relatively inexpensive29 Dr.K.Saminathan.M.Pharm, M.B.A, Ph.D

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VII. PREVENTION OF ANTIBIOTIC RESISTANCEPatients :•Take antibiotics exactly as the doctor prescribes. •Do not skip doses. •Complete the prescribed course, even when you feeling better.•Only take antibiotics prescribed for you. •Do not save antibiotics for the next illness. •Discard any leftover medication once the treatment is completed.•Do not ask for antibiotics to your doctor. •Prevent infections by practicing hygiene and recommended vaccines.

Health professionals:•Do not treat viral infections with antibiotics.•Prescribe antibiotics only when they are absolutely necessary – giving them at the right dose and only for as long as they are needed.•Avoid unnecessary overlaps in antibiotics. •Become familiar with resistance trends in your region.

END30 Dr.K.Saminathan.M.Pharm, M.B.A, Ph.D

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“A drug is a chemical substance that has known

biological effects on humans or other animals”

DRUG IS THE CHEMICAL SUBSTANCE AND USED TO DRUG IS THE CHEMICAL SUBSTANCE AND USED TO

1.PRIVANT DISEASE 1.PRIVANT DISEASE ( vaccine)( vaccine)

2.IDENTIFIED DISEASE 2.IDENTIFIED DISEASE (diagnostic kit)(diagnostic kit)

3. REDUCE/SUPPRESS DISEASE 3. REDUCE/SUPPRESS DISEASE (pain killer)(pain killer)

4. CURE DISEASE 4. CURE DISEASE ( kill the microbes)( kill the microbes)5. CHANGE THE PSYCHOLOGY MOOD 5. CHANGE THE PSYCHOLOGY MOOD

(sleeping tablets)(sleeping tablets)

DRUG


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MINIMAL INHIBITORY CONCENTRATION


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THE MINIMAL BACTERICIDAL CONCENTRATION


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Sir Alexander Fleming, FRSE, FRS, FRCS was a Scottish biologist, pharmacologist and botanist. He wrote many articles on bacteriology, immunology, and chemotherapy.

Born: August 6, 1881, Lochfield

Died: March 11, 1955, London, United Kingdom

Education: St Mary's Hospital Medical School (1903–1906),

Awards: Nobel Prize in Physiology or Medicine, John Scott Legacy Medal and Premium

Children: Robert Fleming

Parents: Grace Stirling Morton, Hugh Fleming


PENICILLINS


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CEPHALOSPORINS


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POLYMYXIN


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CHLORAMPHENICOL


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1. INTRODUCTION OF CHEMOTHERAPY

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