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