Chemotherapy - General Introduction

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Chemotherapy
 Antimicrobial drugs
 Treatment of systemic infections with
specific drugs that can selectively suppress
microbial pathogens without significant
toxicity to host.
Chemotherapy – General Considerations
 Due to analogy between the malignant cell
and the pathogenic microbes, treatment of
neoplastic diseases with drugs is also called
‘chemotherapy’.
Tripathi, K. D. Essentials of Medical Pharmacology. 8th ed., Jaypee Brothers Medical, 2018.
Dept of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal
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History Various terminology

 The history of chemotherapy may be divided
 Chemotherapeutic agents
into 3 phases
 The period of empirical use  Antimicrobials
 chaulmoogra oil by the Hindus in leprosy
 chenopodium by Aztecs for intestinal worms
 Antibiotics
 mercury by Paracelsus (16th century) for syphilis
 Semisynthetic antibiotics
 cinchona bark (17th century) for fevers
 Ehrlich’s phase of dyes and organometallic  Antibacterials, antivirals, antifungal
compounds (1890–1935): dyes that stains,
methylene blue, could kill bacteria  Bacteriostatic
 The modern era of chemotherapy  Bactericidal
 Domagk : 1935 : Prontosil  a sulfa dye
 Fleming: 1929: Penicillin  Fungistatic
 Chain and Florey: 1939-41: Clinical use of Penicillins
 Waksman: 1944: Streptomycin from actinomycetes  Fungicidal
 Pasteur: 1877: “Antibiosis”
3 Dept of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal
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Prokaryotes vs Eukaryotes Prokaryotes vs Eukaryotes

Prokaryotic cell Eukaryotic cell
 Size: 1-10μM  10-100μM Prokaryotic cells
 Single closed
 Rigid cell wall  Plasma membrane compartment
 Subcellular organs  Present  Surrounded by the
absent / indistinct plasma membrane
 Lacks a defined nucleus,
 Enzymes at cell  At mitochondria  A relatively simple
membrane internal organization
 Bacteria, the most
 70S: 30 S and 50S  80s: 60s and 40s numerous prokaryotes,
ribosomes are single-celled
organisms
S= Svedberg unit = 10-13 sec “Measure of sedimentation rate
5 Lodish, Harvey F. Molecular Cell Biology. 4th ed. New York: 6
Dept of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal W.H. Freeman, 2000. Dept of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal
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Prokaryotes vs Eukaryotes Pathogenic microbes classes

 Bacteria
 Higher forms: Actinomycetes, Streptomycetes
 Lower forms: Cocci, Bacilli, Vibrio, Spirilla
Eukaryotic cells  Special: Acid-Fast Bacilli: M. avium, M. tuberculosis, M.
leprae
 Spirochetes: (no rigid cell wall, slender / spiral shaped)
 Treponema pallidium: Syphilis
 Borrelia recurrentis: Body lice, relapsing fever
 Rickettsiae:
 Rigid cell wall, G-ve, Rocky Mountain spotted fever,
typhus fever
 Chlamydiae:
 Rigid cell wall, G-ve, Possess RNA/DNA (Like bacteria),
Grows only inside other cells (Like virus)
 Miscellaneous: M. pneumonia (atypical pneumonia),
Ureaplasma, Pneumocystis carini (AIDS-Pneumonia)
Lodish, Harvey F. Molecular Cell Biology. 4th ed. New York: H L Sharma; K K Sharma, Sharma & Sharma's principles of pharmacology. 3 ed., Paras Medical Publisher, 2017.
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W.H. Freeman, 2000.
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Cocci What about anerobic cocci?

 Gram +  Gram –  Anaerobic Gram-  Anaerobic Gram-
 Staphylococcus  Neisseria positive cocci negative cocci
aureus gonorrhoeae  Peptococcus,  Veillonella,
 Bacteremia,  Gonorrhoea,  Peptostreptococcus,  Acidominococcus,
septicaemia / Urethritis, Cervitis
abscess  Anaerococcus,  Megosphora.
 Streptococcus  Peptoniphilus,
 N. meningitidis
pyogens  Gallicola,
 Meningitis
 Pharyngitis, sinusitis,  Finegoldia,
otitis, rheumatic fever
 Micromonas
 Strepto. faecalis  Moraxella catarrhalis
 Endocarditis, UTI  Sinusitis,
 Strepto. pneumoniae pneumonia, otitis  Anaerobic cocci  Found in human fecal flora
 Normal flora of the human
 Pneumoniae,
oral cavity, alimentary
meningitis, sinusitis
tract, skin and vagina

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Bacilli Bacilli
 Gram –ve: Others (Aerobic)
 Gram +  Gram -ve
 H. influenza: Sinusitis,
 Clostridium tetani: Tetanus  Enterobacteriaeceae bronchitis, pneumoniae,
 E. coli: UTI, Dysentry meningitis
 C. perfringens: Gas gangrene
 S. typhi: Typhoid,  P. aeruginosa: UTI, HAI,
 C. difficle: P. colitis food poisoning Burns
 C. botulinum: Botulism (Food  Shigella:  Y. pestis: Plague
Gastroenteritis,
poisoning) Dysentry
 Brucella abortus:
Brucellosis
 Corynebacterium diphtheria:  Klebsiella: HAUTI,  V. cholera: Cholera
Diphtheriae pneumonia
 Bordetella pertussis:
 H. pylori: Peptic ulcer
 Bacillus anthracis: Anthrax, Whooping cough
pneumoniae
 Bacteroids fragilis: Brain
and lung abscess
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(Anaerobic) 12
Dept of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Dept of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal
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Classification I: Chemical Structure

Classification of antimicrobials
1. Sulfonamides  Dapsone, Sulfamethoxazole
Different ways of classification
2. Diaminopyridines  Trimethoprim, Pyrimethamine
1. Chemical Structure 3. Quinolones  Nalidixic acid, Ciprofloxacin
2. Mechanism of action 4. β lactams  Penicillins, cephalosporins,
3. Type of organisms against which it is monobactams
active 5. Tetracycline  Doxycycline
6. Nitrobenzene derivative: Chloramphenicol.
4. Spectrum of activity
7. AminoglycosidesStreptomycin, gentamicin
5. Type of action 8. Macrolides  Erythromycin, Roxithromycin
6. Source of the antibiotic 9. Lincosamide antibiotics: Lincomycin, Clindamycin.
10. Glycopeptide antibiotics: Vancomycin,
Teicoplanin.
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Classification I: Chemical Structure Class II: Mechanism of Action

11. Oxazolidinone: Linezolid. 1. Inhibits Cell wall synthesis
12. Polypeptides Polymyxin, colistin, Bacitracin β lactams, vancomycin, bacitracin, cycloserine
13. Nitrofurans Nitrofurantoin, Furazolidone 2. Cause Leakage of Cell membranes
Polymyxins, Colistin, bacitracin, amphotericin, nystatin,
14. Nitroimidazoles Metronidazole, tinidazole Hamycin
15. Imidazoles  Miconazole, Clotrimazole 3. Inhibits protein synthesis Tetracyclines,
Chloramphenicol,
16. Nicotinic acid derivatives: Isoniazid, 4. Misreads m-RNA Streptomycin, Gentamicin
Pyrazinamide, Ethionamide. 5. Inhibits DNA gyrase Quinolones
17. Polyene antibiotics: Nystatin, Amphotericin-B, 6. Interferes with DNA functionRifampicin,
Hamycin. Metronidazole
18. Miscellaneous  Rifampicin, Griseofulvin, 7. Inhibits DNA synthesis  Idoxuridine, Acyclovir,
Zidovudine
Ethambutol, Clofazimine 8. Inhibits intermediary metabolism  sulfonamides,
PAS, Trimethoprim, Ethambutol

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Class III: Type of Microbe affected Class IV: Spectrum of activity

1. Antibacterial penicillins,
 Narrow Spectrum
aminoglycosides
2. Antifungal  Griseofulvin,  Penicillin G, Streptomycin,
Amphotericin Erythromycin
3. Antiviral  Idoxuridine, Acyclovir,
Amantadine  Broad Spectrum
4. Antiprotozoal  Chloroquine,  Tetracycline, Chloramphenicol
Pyrimethamine
5. Anthelmentic Mebendezole,
Pyrantel, DEC
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Class V: Type of Action Classifn VI: Source

Primarily Bacteriostatic  Fungal
Sulfonamides, Tetracycline, Chloramphenicol,  Penicillin, Cephalosporin, Griseofulvin
Erythromycin, Ethambutol
 Bacteria
Primarily Bactericidal  Polymyxin, Colistin, Aztreonam
Penicillin, Cephalosporins, Aminoglycosides,  Actinomycetes
Vancomycin, Nalidixic acid, Rifampicin, Isoniazid  Aminoglycosides, Tetracyclines,
Co-trimoxazole Choloramphenicol, Macrolides

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Problems of Chemotherapy 1a. Toxicity : Local

Local
1) Toxicity : a] Local & b] Systemic
 Local: Irritation
2) Hypersensitivity  At site of administration
 Gastric irritation, pain
3) Drug Resistance
 Pain, abscess at site of i.m.
4) Superinfection  Thrombophlebitis
 Most antimicrobials are irritant
5) Nutritional deficiency  Particularly erythromycin, tetracyclines,
some cephalosporins, chloramphenicol
6) Masking of Infections
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1b. Toxicity: Systemic 2. Hypersensitivity

 Most AMA have systemic toxicity
 Safe (high therapeutic index)  Most AMAs cause hypersensitivity
 Penicillin, Cephalosporins [some], Erythromycin
 Safe even at 100 times therapeutic dose  unpredictable and unrelated to dose
 Moderately toxic (lower therapeutic index)  From rashes to anaphylactic shock

 Aminoglycosides 8th cranial nerve, Nephrotoxicity
 Tetracyclines  Liver & kidney damage  Most frequent  penicillins,
 Chloramphenicol  bone marrow depression
cephalosporins, sulfonamides
 Very toxic (very low therapeutic index)
 Polymyxin B  neurological & kidney toxicity
 Vancomycin  hearing loss & Nephrotoxicity
 Amphotericin  kidney, bone marrow, neurological
toxicity
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3. Drug Resistance 3. Drug Resistance

 Acquired resistance:
 “unresponsiveness of a microorganism to
an AMA”  Occurs on prolonged exposure to the AMA
 Natural : Some microbes have always been  Major clinical problem
resistant to certain AMAs
 Depends on both AMA & microbe
 Due to lack of metabolic process or the target site
affected by AMAs  Some microbes are more susceptible to resistance Eg
 gram-negative bacilli are resistant to penicillin-
G tubercle bacteria, staphylococci
 aerobic organisms resistant to metronidazole  Some are less prone: Strep pyogenes still sensitive to
 anaerobic bacteria resistant to aminoglycoside penicillin
antibiotics
 Acquired: It is the development of resistance by an  Gonococci rapidly developed resistance to
organism (which was sensitive before) due to the sulfonamides but slowly to penicillin
use of an AMA over a period of time.
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4. Superinfection (Suprainfection) Superinfection continued

 Appearance of a new infection while treating  More when combinations are used
another  More when host immunity is compromised
 Intestinal microflora inhibit pathogens  Eg corticosteroids, immunosuppressants,
 by a substance called bacteriocin
diabetes, AIDS
 Microflora compete with pathogens for nutrition
 Prolonged use of broad spectrum kills microflora 
 Site of superinfections : oropharynx, intestinal,
superinfection
respiratory, genitourinary tracts
 Killing microflora  normally nonpathogenic  Superinfections  more difficult to treat
components of microflora  becomes pathogenic  Common superinfections
 For eg Candida  Candida albicans  diarrhoea, thrush,
 AMA: Eg. tetracycline, chloramphenicol >> amoxicillin vulvovaginitis
 cause superinfection diarrhoea because of incomplete  Staphylococci  enteritis
absorption, thus higher amounts reach the lower bowel
and cause greater suppression of colonic bacteria.  Clostridium difficile  pseudomembranous
enterocolitis

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Superinfection continued 5. Nutritional deficiencies
To minimize superinfections:  Some of the B complex group of vitamins and

vit K synthesized by the intestinal flora is
1. Use specific (narrow-spectrum) AMA whenever utilized by man.
possible.
 Prolonged use of antimicrobials which alter this
2. Do not use antimicrobials to treat insignificant, flora may result in vitamin deficiencies.
self-limiting or untreatable (viral) infections.  Neomycin causes morphological
abnormalities in the intestinal mucosa—
3. Do not unnecessarily prolong antimicrobial steatorrhoea and malabsorption syndrome
therapy can occur.

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6. Masking of an infection Mechanism of drug resistance

 A short course of an AMA may be sufficient to 1. Mutation:
treat one infection but only briefly suppress 1. Single step
another one 2. Multistep
 The other infection will be masked initially, only

to manifest later in a severe form.
2. Gene transfer:
1. Conjugation
 Syphilis masked by the use of a single dose of
2. Transduction and
penicillin which is sufficient to cure gonorrhoea.
3. Transformation
 Tuberculosis masked by a short course of
streptomycin given for trivial respiratory
infection.
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A. Mutation: A. Mutation
1. Stable and heritable genetic change 1. Single step:
2. Develops spontaneously and randomly  A single gene mutation may confer high degree of
resistance
3. Any sensitive population of a microbe  emerges rapidly,
contains a few mutant cells, which  e.g. enterococci to streptomycin, E. coli and
require higher concentration of the AMA Staphylococci to rifampin
for inhibition. 2. Multistep:
4. Mutant cells proliferate when the  A number of gene modifications are involved
 sensitivity decreases gradually in a stepwise
sensitive cells are eliminated by the manner.
AMA.  E.g. Resistance to erythromycin, tetracyclines
5. Vertical transfer of resistance and chloramphenicol is developed by many
organisms in this manner.
6. Eg: Use of single anti-tubercular drug

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B. Gene transfer (infectious

resistance) 1. Conjugation
1. An important mode of resistance
 The resistance causing gene is passed from
2. Transfer of DNA (chromosomal or plasmid)
one organism to the other; is called horizontal
carrying resistance gene
transfer of resistance.
3. Occurs through the sex pili during conjugation
4. The gene carrying the ‘resistance’ or ‘R’ factor is
 Rapid spread of resistance
transferred only if another ‘resistance transfer
factor’ (RTF) is also present.
 Multidrug resistance 5. More common among gram –ve
6. Occurs more in colon, rich in microflora
7. Sometimes from nonpathogenic to pathogenic
microbes
 chloramphenicol resistance of typhoid bacilli,
 streptomycin resistance of E. coli,
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Mechanism of gene transfer Gene transfer contd..

2. Transduction
 Gene transfer through a bacteriophage
 R factor enters virus, delivered to infected
bacterium
 Occurs in penicillin, erythromycin,
chloramphenicol
3. Transformation
 R factor from a resistant bacterium enters the
medium
 Picked up by a nonresistant bacterium
 Rare eg pneumococcal resistance to
penicillin G
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Nature/type of Resistant bacteria Cross Resistance

1. Drug tolerant: Loss of affinity of the target  Definition: Resistance to one AMA confers resistance
biomolecule of the microorganism for a to a closely related AMA
particular AMA 1. Total cross resistance
1. Loss of AMA target
Eg. Staph aureus, E coli with RNA polymerase that does not bind
 Eg. Sulfonamides & Tetracyclines : resistance to
rifampicin one means resistance to all
2. Altered metabolic pathway 2. Partial cross resistance
Eg. Sulfonamide resistant bacteria switch to using preformed folic
acid instead of synthesizing it  Eg. Resistance to gentamicin but not amikacin
2. Drug destroying: The resistant microbe consists 3. Two way
an enzyme which inactivates the drug  Eg. erythromycin   Clindamycin two way
 β lactamase produced by Staphylococci, Haemophilus, 4. One way
Gonococci
 Aminoglycosides are acetylated, phosphorylated etc
 Neomycin resistance leads to streptomycin
resistance
3. Drug Impermeable
 Hydrophilic AMAs enter through porins  Not vice versa
 Eg. chloroquine resistant falciparum do not take up drug
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Prevention of Drug resistance Choice of an AMA

1. Avoid Indiscriminate use
2. Avoid inadequate use  The choice depends on the particulars of the
patient, the infecting organism and the
3. For acute localized infections in otherwise
drug.
healthy patients, symptom-determined shorter
courses of AMAs are advocated.  Patient factors
4. Use fast acting, selective AMA [Narrow 1. Age
spectrum] 2. Renal and hepatic function
5. Use broad spectrum only when needed 3. Local factors
6. Combination therapy for long term treatment 4. Drug allergy
7. Treat resistance-prone infections intensively 5. Impaired host defence
Eg, Staph aureus, E coli, M tuberculosis, 6. Pregnancy
7. Genetic factors

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Choice of an AMA Patient-related factor

1. Age: Affects the kinetics of AMAs
 Organism-related factors:
A. In newborn: chloramphenicol larger doses
1. Clinical diagnosis itself directs choice of the AMA
produces gray baby syndrome
2. A good guess can be made
3. Choice to be based on bacteriological Examination  Inefficient conjugation and excretion
 Drug factors B. Neonates: Sulfonamides causing kernicterus
1. Spectrum of activity  Displacement of bilirubin from binding sites, which
reaches brain through blood brain barrier (which
2. Type of activity
in not fully developed.)
3. Sensitivity of the organism
4. Relative toxicity C. In elderly: Aminoglycoside toxicity
5. Pharmacokinetic profile  The t½ of aminoglycosides is prolonged in the
6. Route of administration elderly: VIII nerve toxicity
7. Evidence of clinical efficacy D. Child up to 6years: Tetracycline toxicity
 Discoloration of teeth and bone

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Patient-related factor Patient-related factor

3. Local factors: The conditions prevailing at the site of
2. Renal and hepatic function: infection
1. Presence of pus and secretions decrease the
efficacy of most AMAs: especially sulfonamides
and aminoglycosides.
2. Presence of necrotic material or foreign body
including catheters, implants
3. Haematomas foster bacterial growth:
Tetracyclines, Penicillins etc. get bound to the
degraded haemoglobin.
4. pH at the site of action:
 Lowering of pH at the site of infection
reduces activity of macrolide and
aminoglycoside antibiotics.
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Patient-related factor Patient-related factor

5. Impaired host defence
5. Anaerobic environment impairs the bacterial  Pyogenic infections occur readily in neutropenic
transport processes patients.
 Aminoglycosides activity will reduce  Bacteriostatic AMA for normal host defence whereas
6. Penetration barriers at certain sites may cidal drugs for impaired defence
hamper the access of the AMA to the site, 6. Pregnancy
such as in subacute bacterial endocarditis  All AMAs should be avoided.
(SABE)  Penicillins, many cephalosporins and erythromycin
are safe
 4. Drug allergy: e.g. drug of choice for syphilis  Tetracyclines and Aminoglycosides are clearly
in a patient allergic to penicillin is tetracycline. contraindicated
7. Genetic factors: Primaquine, nitrofurantoin, sulfonamides,
chloramphenicol and fluoroquinolones carry the risk of producing
haemolysis in G-6-PD deficient patient.

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Organism-related considerations Drug factors

1. Clinical diagnosis itself directs choice of the 1. Spectrum of activity
AMA: tuberculosis, amoebiasis  For definitive therapy: Narrow spectrum AMAs
2. A good guess can be made  For empirical therapy (No information about the
bacteria), often a broad-spectrum drug
 clinical features and local experience
3. Choice to be based on bacteriological 2. Type of activity
examination:  several acute infections resolve faster with a cidal
than a static drug
 e.g. bronchopneumonia, meningitis,  A bactericidal antibiotic is superior to bacteriostatic
osteomyelitis, urinary tract infection, wound drug in treating patients with impaired host defence,
infection, etc. (culture and sensitivity life-threatening infections
testing) 3. Sensitivity of the organism :
MIC values
4. Relative toxicity
 A less toxic antibiotic is preferred, e.g. a β-lactam
49 over an aminoglycoside
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Drug factors Drug factors

5. Pharmacokinetic profile  6. Route of administration:
 ‘concentration-dependent killing’  Certain AMAs are only effective parenterally
 Aminoglycoside, vancomycin, penicillin-G
 Aminoglycosides, FQs etc  Oral antibiotics: For less severe infections
 ‘time-dependent killing’  Parenteral: For severe infections
 Beta-lactams, glycopeptides, macrolides
 Penetration  7. Evidence of clinical efficacy
 FQs have excellent tissue penetration-attain  Reliable clinical trial data
high concentrations in soft tissues
 Cefuroxime, ceftriaxone in CSf  8. Cost-effectiveness: Less expensive drugs are
 Penicillines and aminoglycosides have poor to be preferred.
CSF penetration but effective in meningitis

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Antimicrobial Combinations Advantages of combinations contd..

 Advantages (Objectives) of combined therapy
1. Synergism
 A. To achieve synergism
2. Reduce ADR
3. Prevent resistance  If the MIC of each AMA is reduced to 25% or less,
4. Broaden spectrum the pair is considered synergistic,
 Disadvantages  IF MIC is 25–50% of each is considered additive
 Promote a casual rather than rationale outlook in and
diagnosis / choice of AMA
 More than 50% of MIC of each indicates
 May increase incidence of ADRs
antagonism.
 Increase superinfections
 Emergence of resistant organisms in inadequate doses
 Increased cost
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COMBINED USE OF ANTIMICROBIALS COMBINED USE OF ANTIMICROBIALS
 Possible combinations  Bactericidal + Bacteriostatic

 Bacteriostatic + Bactereostatic  (i) If the organism is highly sensitive to the
cidal drug—response to the combination is
 Additive: Tetracycline + Chloramphenicol
equal to the static drug given alone (apparent
 Supra-additive effect (cidal): antagonism)
Sulphonamide + Trimethoprim  Penicillin + tetracycline/chloramphenicol on
(Sequential blockade) pneumococci which are highly sensitive to penicillin.
 Because cidal drugs act primarily on rapidly
multiplying bacteria, while the static drug retards
 Bactericidal + Bactericidal multiplication.
 Penicillin + Aminoglycoside, INH+ Rifampin  (ii) If the organism has low sensitivity to the
(frequently additive and sometime cidal drug—synergism may be seen
synergistic)  Penicillin + sulfonamide for actinomycosis
 Rifampin + dapsone in leprosy.
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Advantages of combinations contd.. Disadvantages

B. Reduces ADRs  1. They foster a casual rather than rational
Combinations help reduce dose  ↓ ADRs outlook in the diagnosis of infections and choice
of AMA.
Eg Streptomycin + Penicillin G in bacterial  2. Increased incidence and variety of adverse
endocarditis effects. Toxicity of one agent may be enhanced
C. Reduces emergence of resistance by another, e.g. vancomycin + tobramycin and
gentamicin + cephalothin produce exaggerated
INH + Rifampin + Pyrazinamide in kidney failure.
Tuberculosis  3. Increased chances of superinfections.
D. Broaden spectrum  4. If inadequate doses of nonsynergistic drugs
are used—emergence of resistance may be
Useful in severe infections, mixed infections promoted.
 5. Higher cost of therapy.

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Prophylactic use of AMA Failure of AMAs

 Against specific organisms  1. Improper selection of drug, dose, route or
 Tuberculosis in high risk children duration of treatment.
 Malaria in endemic areas
 2. Delay in starting the treatment.
 Meningiococcal meningitis
 3. Failure to take necessary adjuvant
 Prevention in high risk situations
measures, e.g. drainage of abscesses
 Surgery
 Dental extraction, endoscopy,  4. Poor host defence—as in leukaemias
 Catheterisation  5. Accessibility: Barriers, eg. SABE
 Immunocompromised patients  6. Trying to treat untreatable (viral) infections
× Prevention of infection in general  7. Presence of dormant or altered organisms
× Neonates after instrumental delivery
× Elective surgery
× Unconscious patients (for respiratory
infections)
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27/03/2022

History Various terminology

Prokaryotes vs Eukaryotes Prokaryotes vs Eukaryotes

Prokaryotes vs Eukaryotes Pathogenic microbes classes

Cocci What about anerobic cocci?

Dept of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal

Classification I: Chemical Structure

Classification I: Chemical Structure Class II: Mechanism of Action

Dept of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal

Class III: Type of Microbe affected Class IV: Spectrum of activity

Class V: Type of Action Classifn VI: Source

Dept of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal

Problems of Chemotherapy 1a. Toxicity : Local

1b. Toxicity: Systemic 2. Hypersensitivity

 Moderately toxic (lower therapeutic index)  From rashes to anaphylactic shock

3. Drug Resistance 3. Drug Resistance

4. Superinfection (Suprainfection) Superinfection continued

Dept of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal

Superinfection continued 5. Nutritional deficiencies

To minimize superinfections:  Some of the B complex group of vitamins and

Dept of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal

6. Masking of an infection Mechanism of drug resistance

 The other infection will be masked initially, only

Dept of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal

B. Gene transfer (infectious

Mechanism of gene transfer Gene transfer contd..

Nature/type of Resistant bacteria Cross Resistance

Prevention of Drug resistance Choice of an AMA

Dept of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal

Choice of an AMA Patient-related factor

Dept of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal

Patient-related factor Patient-related factor

Patient-related factor Patient-related factor

Dept of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal

Organism-related considerations Drug factors

Drug factors Drug factors

Dept of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal

Antimicrobial Combinations Advantages of combinations contd..

 Emergence of resistant organisms in inadequate doses

COMBINED USE OF ANTIMICROBIALS COMBINED USE OF ANTIMICROBIALS

 Possible combinations  Bactericidal + Bacteriostatic

Advantages of combinations contd.. Disadvantages

Dept of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal

Prophylactic use of AMA Failure of AMAs

Dept of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal

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