Basics of Chemotherapy

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PHAR1001 Pharmacology
Basics of Chemotherapy Antibiotics, resistance
and combination therapy
Dr Dean Willis Department of Pharmacology Universi
ty College London Gower Street, London WC1
6BT dean.willis_at_ucl.ac.uk
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Aims
Review Chemotherapy idea.
To understand the term antibacterial drug.
Understand the factors influencing antibacterial
selection.
Know the 3 basic sites of action of the
antibacterial drugs.
Understand the bases of resistance to these drugs.
Understand the bases of combination therapy.
Pharmacology. Rang, Dale, Ritter Moore 5th
Edition Chapters. 44 45
Integrated Pharmacology. Page, Curtis, Sutter,
Walker Hoffman 2nd Edition Chapters 9
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Theory of Chemotherapy. The Idea
Find Qualitative (preferable) or Quantitative
Biochemical difference between Host and Parasite
which when exploited by a selective drug results
in a cytotoxic effect to the parasite but not host
Theory
Drug
Host
Parasite
No effect
Cytotoxic
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Theory of Chemotherapy. The Targets
Class I Biochemical reactions (energy production)
Gycolysis, Catabolism of polysaccharides and
lipids, pentose phosphate pathway, pyruvate
oxidation, citric acid cycle, fermentation and
respiration
Class II Biochemical reactions (Small molecule
synthesis)
Biosynthesis of amino acids, Lipids, Coenzymes
(tetrahydrofolate), Purines Pyrimidines, heme
catabolism/metabolism
Class III Biochemical reactions (Macromolecule
production, polymers)
Biosynthesis of DNA, RNA, proteins, Lipoproteins,
peptidoglycans protein degradation, Cytoskeleton
assembly, Glycogen synthesis,
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History of antibacterial antibiotics agents
Louis Pasteur 1822-1895 Chemist
germ theory of disease 1877
1928 Alexander Fleming (mold Penicullium
destroyed S. aureus) However Ernest Duchesne had
discovered the antibiotic properties of
Penicullium in 1892
1932 Gerhard Domagk discovered antibacterial
effects of Sulphonamides
1942 Chain Florey first use of penicillin in
clinics
1945 Fleming predicts resistance could be problem
of the future
By products of micro-organisms (antibiotics) Human
designed drugs (Chemotherapeutic or synthetic
drugs) Hybrid of the two (Semi-synthetic agents)
Antibacterials
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Factors influencing antibacterial selection
action.
Target of action.
Prokaryotes
DNA (chromosome)
No mitochondria
Ribosomes
Cell membrane
Cell wall
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Factors influencing antibacterial selection
action.
Concentration.
Antibiotic spectrum activity.
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Antibacterial Drug targets
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The Folate pathway for antibacterial agents
C50 (mmol/l) for FH2 reductase
Human
Protozoal
Bacterial
Trimethoprim
260
0.07
0.005
Pyrimethamine
0.7
0.0005
2.5
Methotrexate
0.001
0.1
inactive
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b-lactam antibacterials
O
S
NAMAN-acetylumuramic acid NAGN-acetylglucosamine
NH
C
N
COOH
O
b-lactamase
Penicillin Nucleus
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Antibacterial drugs affecting protein synthesis
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RESISTANCE
Conjugation. Chromosomal plasmid DNA
Transduction. Virus, bacteriaphage
Tranformation. Naked DNA
Point Mutation.
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Mechanisms of Drug Resistance
Concentration of Drug
Inactivate Drug
Prevent uptake of Drug
Promote efflux of drug
Altered Drug Target
Bypass Metabolic Requirement for Target
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Combinational therapy
Individual drugs must active against the drug
Individual drugs must target different
biochemical pathways
Individual drugs must not have overlapping
toxicity profiles
Therapeutic regimes are tailored to the
individual
Example malaria
Sulfonamides Pyrimethamine Chloroquine
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Highly active anti-retroviral therapy (HAART)