Introduction of chemotheraphy

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INTRODUCTION OF CHEMOTHERAPHYINTRODUCTION OF CHEMOTHERAPHY

BYBY

K.SAMINATHAN. M.PHARM.(PhD), M.B.A .(PhD)K.SAMINATHAN. M.PHARM.(PhD), M.B.A .(PhD)

LEARNING OBJECTIVES

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I. DEFINITIONS

II. HISTORY

III. MECHANISMS OF ANTIMICROBIAL AGENTS

IV. MECHANISMS OF ANTIBACTERIAL RESISTANCE

V. GENERAL PRINCIPLES OF ANTI-INFECTIVE

THERAPY

VI. IDEAL ANTIMICROBIAL DRUG

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I.DEFINITIONS

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

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.

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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.

Today the term antibiotic extends to include synthetic antibacterial agents: sulfonamides and quinolones.

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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 )

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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.

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II.HISTORY1929 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

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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

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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 toxicity

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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.

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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.

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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.

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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.

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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.

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TYPES OF RESISTANCE

• Intrinsic or natural resistance• e.g., no target site in the bacteria

• Acquired resistance–Resistance acquired by mutation is unusual,–Resistance acquired by R-factors on plasmids is common, very rapid method of acquiringresistance that often involves resistance tomany antibiotics. (R factor contains genescoding for enzymes that make the cell resistant to antibiotics)

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MECHANISMS OF ANTIBACTERIAL RESISTANCE

① Produce enzymes that destroy thechemical structures of drugs

② Change their cell membrane and cellwall permeability to the drug

③ Develop an altered structural targetfor the drug④ Develop an altered metabolic pathway

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1. Mechanisms of antibacterial resistance

• Antibiotic inactivation– bacteria acquire genes encodingenzymes that inactivate antibiotics

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

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2. 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.

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3. 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.

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4.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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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 distributionBe free of interactions with other drugs.Be relatively inexpensive