prinicples of chemotherapy
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CHEMOTHERAPY
KRVS Chaitanya
CONTENT 1. Introduction And Definition2. History3. Classification4. Mechanism Of Action5. Type Of Organism Against Which Primarily Active6. Spectrum Of Activity7. Type Of Action 8. Antibiotics- Source9. Problems Arising With Use Of AMAs
• Antimicrobial drugs are the greatest contribution of the 20th century to therapeutics• Importance is magnified in developing countries where infective
diseases predominate• As a class, they are one of the most frequently used as well as misused
drugs
Antibiotics -
• These are substances produced by microrganisms, which selectively suppress the growth of or kill other microrganisms at very low concentrations
• Chemotherapeutic agent • Antimicrobial agent (AMA)
HISTORY – divided into 3 phases
A. Period of empirical use - * ‘ mouldy curd ’ on boils , chaulmoogra oil by the hindus in leprosy , chenopodium by aztecs for intestinal worms , mercury by Paracelsus (16th century) for syphillis , cinchona bark (17th century) for fever.
B. Ehrlich’s phase of dyes and organometallic compounds ( 1890 – 1935 ): discovery of microbes in later half of 19th century – arsenicals – atoxyl for sleeping sickness and arsphenamine & neoarsphenamine for syphillis – coined the term ‘chemotherapy’
C. Modern era of chemotherapy –domagk-demonstrated therapeutic effect of prontosil PYOGENIC INFECTION
- Penicillium mould destroy staphylococcus – fleming (1929)- penicillin
- Chain & Florey (1939) – purified the penicillin – 1st clinical use of penicillin (1941)
- Waksman ( 1944) – systematic search of actinomycetes as source – streptomycin
A. Mechanism of action -1. Inhibit cell wall synthesis : Penicillins, Cephalosporins, Cycloserines, Vancomycin, Bacitracin
2. Cause leakage from cell membranes : Polypeptides- Polymyxins, Colistin, Bacitracin. Polyenes- Amphotericin B,
Nystatin , Hamycin
3. Inhibit protein synthesis : Tetracyclines, Chloramphenicol, Erythromycin, Clindamycin, Linezolid
4.Misreading of m-RNA and affect permeability : Aminoglycosides – Streptomycin, Gentamicin Etc.
5. Inhibit DNA gyrase – Fluoroquinolones-ciprofloxacin and others
6. Interfere with DNA function – Rifampin, Metronidazole
7. Interfere with DNA synthesis – Acyclovir, Zidovudine
8. Interfere with intermediary metabolism – Sulfonamides, Sulfones, PAS, Trimethoprim, Pyrimethamine, Metronidazole
B. Type of organisms against which primarily active -1. Antibacterial : penicillins, aminoglycosides, erthryomycin,
fluoroquinolones etc.2. Antifungal : griseofulvin, amphotericin B, ketoconazole, etc3. Antiviral : acyclovir, amantadine, zidovudine etc.4. Antiprotozoal : chloroquine, pyrimethamine, metronidazole,
diloxanide etc.5. Antihelminthic : mebendazole, pyrantel, niclosamide, diethyl
carbamazine etc.
C. Spectrum of activity -
Narrow spectrum
Penicillin GStreptomycinErythromycin
Broad spectrum
TetracyclinesChloramphenico
l
Type of action • Primarily bacteriostatic –
Sulfonamides Erythromycin Tetracyclines ClindamycinChloramphenicol Linezolid Ethambutol• Primarily bactericidal –
Penicillins CephalosporinsAminoglycosides Vancomycin Polypeptides CiprofloxacinRifampin MetronidazoleIsoniazid CotrimoxazolePyrazinamide
Antibiotics are obtained from :• Fungi –Penicillin Griseofulvin Cephalosporin
• Bacteria –Polymyxin B Tyrothricin Colistin AztreonamBacitracin
• Actinomycetes –Aminoglycosides MacroglycosidesTetracyclines PolyenesChloramphenicol
Problems that arise with use of AMAs
1. TOXICITY
a) Local irritancy
b) Systemic toxicity – high therapeutic index – penicillins , some cephalosporins and erythromycinlower therapeutic index – aminoglycosides , tetracyclines , chloramphenicolvery low therapeutic index - polymyxin B , vancomycin , amphotericin B
2. HYPERSENSITIVITY REACTIONS
3.DRUG RESISTANCE - a) Natural resistance b) Acquired resistance c) cross resistance
4. NUTRITIONAL DEFICIENCIES
5. MASKING OF INFECTION
6.SUPERINFECTION (Suprainfection) –Appearance of new infection as a result of antimicrobial therapy common when host defence is compromised
Conditions predisposing to superinfections – Corticosteroid therapy Leukemias and other malignanciesAIDSAgranulocytosisDiabetes
1. Genetic methods of Antibiotic resistance - A. Chromosomal Methods : Mutations
B. Extrachromosomal Methods : Plasmids r-genes R-plasmidsPlasmids which carry genes resistant to antibiotics
METHODS –i. Transfer of r-genes from one bacterium to another – 3 mechanisms –
CONJUGATION , TRANSDUCTION & TRANSFORMATION
ii. Transfer of r-genes between plasmids within the bacterium – * by Transposons * by Integrons
TRANSPOSONS – Transposons are DNA segments that cannot self-replicate but can self-
transfer between plasmids or from plasmid to chromosomesDonor plasmid containing a Transposon , cointegrates with the target
(acceptor) plasmidDuring the process of cointegration the transposon can now replicate Both plasmids then separate and each contains the r-gene carrying the
transposon
• By INTEGRONS – Mainly the MDR , can also be spread by a larger mobile DNA unit called
“integrons”
Each integron is packed with multiple gene cassettes, each consisting of a resistant gene attached to a small recognition site
These gene cassettes are encoded with several bacterial functions including resistance and virulence
Currently , the gene cassettes have been identified for all antibiotics except fluoroqinolones
2. Biochemical mechanisms of resistance to Antibiotics -A. By producing an enzyme that inactivates the antibiotic * inactivation of β - lactam antibiotics * inactivation of Chloramphenicol * inactivation of Aminoglycosides B. Prevention of Drug accumulation in the Bacterium C. By Modification/Protection of the target site D. Use of alternative pathways for metabolic/growth requirementE. By Quorum Sensing
• Patient factors – 1. Age 2. Renal and hepatic function 3. Local factors4. Drug allergy5. Impaired host defence6. Pregnancy 7. Genetic factors
Choice of an Antimicrobial Agent -
•Drug factors – 1. Spectrum of activity2. Type of activity3. Sensitivity of the organism4. Relative toxicity 5. Pharmacokinetic profile 6. Route of administration7. Evidence of clinical efficacy8. Cost
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