CHEMOTHERAPY KRVS Chaitanya
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