Chemotherapy Flashcards
What is the concept of an antibiotic
typically antibacterial or antifungal drugs, interfering with some structure or process that is essential to growth or survival of these organisms without harm to the eukaryotic host harbouring the infecting cells.
How have most of the antibiotics in the last 60 years come about
natural products, elaborated by one microorganism in a particular habitat and set of environmental conditions to affect neighbouring microorganisms, either to regulate their growth or to trigger their elimination.
What are the 3 main classes of synthetic antibiotic
Give an example of each and their introduction date
sulfa drugs (such as sulfamethoxazole), introduced in the 1930s,
fluoroquinolones (such as ciprofloxacin), introduced in the 1960s,
oxazolidinone (linezolid), approved in the USA in 2000.
What dichotomy does the existence and clinical development of both synthetic and natural product antibiotics reflect in the 20th century
At one end of the spectrum was the medicinal chemistry view and the
classical “magic bullet” approach, initiated by Ehrlich, that pure
compounds could be made with therapeutic specificity and utility
At the other end of the spectrum, and from a separate track, came the isolation of penicillin (by Fleming in 1929), a natural product, as a potent antibacterial agent
Which type of antibiotic was a triumph for Ehrlich’s ‘magic bullet’ approach
sulfa drugs
Why was the isolation of penicillin important
led to the recognition of the paradigm that microbes wage war against each other with antibiotics
Name 8 antibiotic drug classes which stemmed from the realization that microbes wage war on each other
penicillins and cephalosporins,
tetracyclins,
streptomycins
and later generations of aminoglycosides,
chloramphenicol, rifamycins,
glycopeptides
the erythromycin class of macrolide antibiotics
What does broad or narrow range mean?
those that kill or inhibit a wide range of Gram-positive and Gram-negative bacteria are said to be broad spectrum.
If effective mainly against Gram-positive or Gramnegative bacteria, they are narrow spectrum.
If effective against a single organism or disease, they are referred to as limited spectrum.
When did the 2 strands of antibiotic discovery converge
with the introduction of later generations of semisynthetic variants of b-lactam antibiotics and macrolides, in which chemistry is used to engineer some desired new property, such as oral bioavailability, increased stability, broader spectrum of activity (referred to as extended spectrum), or efficacy against resistant microorganisms.
From 2000 to 2010, how did the use of last resort antibiotics change
increased consumption of carbapenems (45%) and polymixins (13%)
Antibiotic use increased by 36% from 2000 to 2010, where was this mainly accounted for? How can we stop this?
Brazil, Russia, India, China, and South Africa accounted for 76% of this increase
programmes that promote rational use through coordinated efforts by the international community should be a priority
bactericidal vs bacteriostatic
antibiotics that stop bacteria or fungi from growing are bacteriostatic, exemplified by chloramphenicol.
Antibiotics that cause cell death are
bactericidal; they lower the cell count of the infecting organism, as shown for penicillin
When would you use bactericidal drugs over bacteriostatic antibiotics?
when the immune system is compromised as bacteriostatic antibiotics require the bacteria to be eliminated by the immune system
Can a drug be both bacteriostatic and bactericidal
Some antibiotics can display bacteriostatic activity in some circumstances and bactericidal activity in others, where sufficient damage to one or more metabolic pathways or cellular structures occurs such that a net bactericidal response is triggered
What is the MIC and MBC for antibiotics
minimal inhibitory concentration (MIC): lowest concentration of a drug that prevents growth of a particular bacterium.
The minimal bactericidal concentration (MBC) is the lowest concentration that kills the bacterium
Discriminate between selective toxicity and therapeutic index
selective toxicity: growth of the infecting organism is selectively inhibited or killed without damage to the cells of the host
therapeutic ratio: the ratio of the maximum non-toxic dose over the minimum effective dose of a drug.
What is the selective toxicity and therapeutic index of penicillin
What drug has a selective toxicity and therapeutic index that is the opposite of this
high degree of selective toxicity, which corresponds with a large therapeutic index
Polyene antibiotic (eg amphotericin B) have both a low degree of selective toxicity and a low therapeutic index
Are the examples of penicillin and polyene antibiotics representative of most antibiotics’ selective toxicity and therapeutic index relationship?
Give an example
no
there is often little relationship between selective
toxicity and therapeutic index.
aminoglycosides
Describe the selective toxicity and therapeutic index of aminoglycosides
very selective with respect to killing bacterial versus host cells, but for some members of this class, unrelated effects on the patient’s nervous system, kidneys, or inner ear (hearing, balance) result in a much lower margin for therapeutic error that would be predicted on the basis of their selective action on cell viability
Where does the selectivity of anthracyclines come from
differential accumulation:
some tumour cells have enhanced rates of glycolysis, and as a result, reduced pH. Drugs (e.g., anthracyclines) that are trapped in the cell through protonation (thus becoming cationic) are accumulated more in tumour cells than in normal cells.
Give an example of differential activation in cancer chemotherapy
drugs that are activated by reduction (e.g. alkylating agent Mitomycin C), have enhanced toxicity in hypoxic tumour cell in solid tumours
How can cancer drug selectivity be based on differential importance
Alkylating and cross-linking agents, antimicrotubule drugs and antifolates are effective because cancer cells have a high demand in DNA replication and cell
division.
Antibodies and small molecule inhibitors target signaling pathways that are permanently switched on in cancer cells.
What are the 4 major targets for antibiotic drugs
(i) cell wall biosynthesis (sometimes membrane is targeted),
(ii) protein biosynthesis,
(iii) DNA replication, repair and expression
(iv) folate coenzyme
biosynthesis
One guiding concept for selectively killing bacteria while sparing the mammalian
host would be for the antibiotic to act against a target present in bacteria but not
found in animals or humans. Which antibiotic types is this true for
bacterial cell wall biosynthesis targetters
Enzymes in protein biosynthesis, DNA replication, repair and expression, and folic acid synthesis clearly have mammalian counterparts, but there are enough structural differences between the prokaryotic and eukaryotic synthesis machineries that selective inhibition is achievable.