the medicine Flashcards
1
Q
what is the definition of a bacteria
A
Prokaryotic organism (no nucleus).
2
Q
what is a Gram-positive microorganisms
A
have cell walls that
contain thick layers of peptidoglycan amounting to
about 90% of the cell wall. → appear blue to purple
under a Gram stain
3
Q
what are Gram-negative microorganisms
A
have cell walls with thin layers
of peptidoglycan (10% of the cell wall) and high lipid content.
appear red to pink under a Gram stain
4
Q
what are Protozoa (protists)
A
Non-photosynthetic
unicellular organisms with protoplasm
differentiated into nucleus and cytoplasm
5
Q
what are fungi
A
non-photosynthetic organisms that
possess relatively rigid cell walls (chitin).
6
Q
what is a virus
A
infects other cells and requires host cell
machinery to replicate
7
Q
what are natural antibiotics
A
Natural antibiotics occur in nature, they are
produced by one microorganism to selectively
inhibit the growth of others. (e.g. penicillin G/V)
8
Q
what are semi synthetic abs
A
Semi-synthetic antibiotics are chemically
modified natural antibiotics (e.g. ampicillin).
Some agents are not produced naturally, they
are totally synthetic
9
Q
name a narrow spectrum abs
A
vancomycin
10
Q
what is selective toxicity
A
- More damage to the pathogen than to the host (e.g. microorganism vs
human) - More broadly - beneficial effect greater than any detrimental effects
- Not absolute – there are always unwanted side-effects.
11
Q
equation for theraputic index?
A
Therapeutic Index = 𝑇𝑜𝑥𝑖𝑐 𝑑𝑜𝑠𝑒 /
𝑇ℎ𝑒𝑟𝑎𝑝𝑒𝑢𝑡𝑖𝑐 𝑑𝑜𝑠𝑒
- Also known as the therapeutic ratio
- The more potent the drug, the lower the
dose required.
12
Q
list indications for naproxen
A
Naproxen - Upset stomach, ulcer, nausea, heartburn, headache, drowsiness, dizziness
13
Q
list indications for omeprazole
A
Omeprazole - diarrhoea, nausea, constipation, abdominal pain, vomiting, headache,
susceptibility to C. difficile
14
Q
who is Paul Ehrlich (1854-1915)
A
“Magic Bullet” (arsphenamine
for the treatment of syphilis)
15
Q
who are arterial blood gasses tests and checks done on
A
These tests are ordered for patients who: -
are showing signs of respiratory disease
who may have a metabolic condition
Have kidney disease
Suspect that they may have diabetic
ketoacidosis
Patients who are undergoing surgery and
undergo prolonged anaesthesia
16
Q
what is the procedure of retrieving arteial blood gasses
A
Procedure involves drawing blood from
usually the radial artery from a patient’s non-
dominant hand.
Heparinised self-filling
syringe and needle used
17
Q
what is H2CO3
A
carbonic acid
18
Q
what is the normal pH value
A
7.35
19
Q
give an example of a volatile acid
A
carbon dioxide
20
Q
give examples of a non volatile acid
A
Metabolic Acids e.g. Lactic acid, keto acids, uric
acid
21
Q
Buffer definition
A
a buffer solution resists changes in pH
when small quantities of an acid or an alkali are added to it
22
Q
Extracellular Fluid
A
Carbonic Acid Buffer
23
Q
Intracellular Buffer
A
Proteins
Blood Stream: Haemoglobin Buffer
24
Q
physiological buffers in
Renal Tubule
A
Phosphate & Ammonia
25
what can a buffer system not do
buffer itself
26
what is a Bronsted-Lowry acid
acid a substance capable of donating
a proton;
27
what is a lewis acid
electron acceptor
28
what is a Bronsted-Lowry base
base a substance capable of accepting a proton
29
what is aa lewis base
electron donor
30
strength of an acid is measured by
Strength of an acid is measured by the ability to donate protons
Water is an amphiprotic solvent: can accept and donate protons
31
H2PO4- is termed as?
titratable acidity
32
what are protons buffered by
histidine residues
33
explain haemoglobin blood buffers
Haemoglobin carries O2 from the lungs to the muscles through the blood.
The muscles produce CO2 and H+
The buffering action of haemoglobin picks up the extra H+ and CO2.
If haemoglobin buffer is exceeded, the pH of the blood is lowered, causing
acidosis.
34
explain the ideal buffer
equal concs of acid and base
35
what % do Central Chemoreceptors drive
70-80%
36
what % do Peripheral Chemoreceptors drive
20-30%
37
describe renal regulation of pH
Reabsorption of bicarbonate HCO3-
Secretion of protons
Facilitated by Carbonic Anhydrase
38
tell me about tubular buffers bicarbonate
filtered, normally fully
reabsorbed in PCT
39
tell me about tubular buffers phosphate
filtered, major buffer in the
DCT
40
tell me about tubular buffers ammonia
generated allows continued H+
secretion when phosphate buffer
exhausted
ammonium ion is quarternary
highly charged and has very
low lipid solubility i.e. trapped
in the tubular fluid
41
pH referance range
pH = 7.35 – 7.45
42
PaCO2 referance range
PaCO2 = 4.7 – 6.0kPa
(35 - 45 mmHg)
43
PaO2 referance range
PaO2 = 10 – 13kPa
(70 – 100 mmHg)
44
HCO3- refernace range
[HCO3-] = 22 – 26mmol/L
45
SaO2 referance range
SaO2 = 96 – 98% (in adults)
Sa = saturation
expressed as a %
46
what is Acidosis
pH falls below 7.35
so, increasing H+ from either too much pCO2 or
too little HCO3-
47
what is Alkalosis
pH rises above 7.45
vice-versa, i.e. decreasing H+ from reduced
PCO2 or increased HCO3-
48
PaCO2 = Partial pressure of carbon dioxide
is the
measurement of CO2 in the blood – which reflects alveolar
ventilation. If the pH and PaCO2 change in opposite
directions, the primary disorder is respiratory
49
PaO2 = Partial pressure of oxygen - is
is the amount of
oxygen dissolved in the blood and represents gas
exchange in the blood.
50
SaO2 = Oxygen saturation
ratio of oxygen bound to
haemoglobin.
51
what is pH
determines the concentration of hydrogens found in
arterial blood.
52
HCO3- Bicarbonate is
he metabolic component in an
ABG and represents the concentration of hydrogen
carbonate in the blood. If the CO3- and the pH changes in
the same direction, the primary disorder is of a metabolic
component
53
what is Base excess
another measure used to determine the
metabolic component of an acid-base disturbance, and all
bases are measured. It is calculated using blood pH and
PaCO2. It increases in metabolic alkalosis and decreases
in metabolic acidosis.
54
what is Metabolic Disorder
Involves non-volatile acid or altered HCO3-
55
what is Respiratory Disorder
Primary change is in plasma CO2 (Volatile Acid)
56
what is Plasma Buffers disorder
more effective in acidosis
than alkalosis
57
Decreased Acid Secretion cause of acidosis
Renal Failure
Type 1 Renal Tubular Acidosis (DCT)
Hypoaldosteronism (Type 4 renal tubular
acidosis)
58
Increased Metabolic Acid Production cause of acidosis
Lactic acidosis
Ketoacidosis –uncontrolled diabetes mellitus
Ingestion of Acidic material e.g. aspirin
59
Loss of Bicarbonate cause of acidoisis
Diarrhoea and loss of intestinal bicarbonate
Type 2 renal tubular acidosis (PCT)
60
Metabolic Acidosis tell me about it
Cause: Loss of [HCO3-] or addition of acid
Primary Condition: pH; [HCO3-]; -ve Base XS.
First Correction: intracellular/extracellular buffering
Respiratory Compensation: pH ( CO2).
Hyperventilation moves [HCO3-] /pCO2 → 20/1
Renal Correction: delayed by respiratory
compensation
61
Gastrointestinal Hydrogen Loss cause of alkalosis
Loss of gastric secretion – e.g. vomiting
62
Urinary Loss of Hydrogen cause of alkalosis
Loop or Thiazide Diuretics
Hyperaldosteronism
63
Movement of H+ into Cells cause of alkalosis
Hypokalaemia
64
causes of metabolic alkolosis
Administration of Bicarbonate or an
organic ion metabolised to Bicarbonate
(e.g. citrate)
65
tell me more about metabolic alkolosis
Primary Condition: pH; [HCO3-]; +ve Base
XS. XS [HCO3-]; or loss of acid
First Correction: intracellular and extracellular
buffering
Respiratory Compensation: due to CO2 and
pH. Hypoventilation moves [HCO3-] /pCO2 → 20/1
Renal Correction: delayed by respiratory
compensation
66
respiratory acidosis causes
Causes – Lung disorder
COPD – Emphysema
COPD – Bronchitis
Severe Asthma
Pneumonia
Pneumothorax
Causes – Neuromuscular causes
Diaphragm dysfunction and paralysis
Guillain-Barré Syndrome
Myasthenia Gravis
Chest wall causes
Severe kyphoscoliosis
Flail chest
Drugs – that cause respiratory depression
Opioids, narcotics, barbituates, benzodiazepine and other CNS
depressants
67
what are three types of mixing
random, ordered and perfect mix
68
consequenses of respiratory acidosis
ACUTE
HYPERCAPNIA
renal compensation leads to
CHRONIC HYPERCAPNIA
69
tell me about respiratory alkolosis when renal compensation occurs
Renal Compensation: reduced H+ excretion and
bicarbonate reabsorption
At full compensation both buffer components are
depressed and there is positive base excess
70
Respiratory Alkalosis - causes
Causes – Central nervous system
Head injury
Cardiovascular accident (CVA)
Anxiety (hyperventilation syndrome)
Supra-tentorial (e.g. pain, fear, stress)
Pyrexia
Chronic liver failure
71
respiratory acidosis signs and symptons
Anxiety.
Blurred vision.
Confusion.
Discolored (blue, purple, gray-green, grey or white) skin tone from lack of oxygen (cyanosis).
Headache.
Shortness of breath (dyspnea).
Wheezing.
72
respiratory alkolosis signs and symptoms
Breathlessness.
Dizziness.
Numbness and /or tingling in your fingertips, toes and lips.
Irritability.
Nausea.
Muscle spasms or twitching.
Fatigue.
Dizziness/lightheadedness.
73
what happens when CO2 is high
< 7.35
acidosis
respiratory acidosis
74
what happens when HCO3- is low
bicarbonate
< 7.35
acidosis
metabolic acidosis
75
what happens when CO2 is low
> 7.35
alkalosis
respiratory alkalosis
76
what happens when HCO3- is high
Bicarbonate
> 7.35
alkalosis
metabolic alkalosis
77
normal value for PaO2
> 10.6 kPa
78
normal value for PaCO2
4.6 - 6.0 kPa
79
normal HCO3 values
22 - 28 mmol/L
80
when does respirtatory compensation occur
metabolic alkolisos = co2 is high
metabolic acidosis = co2 is low
81
when does metabolic compensation occur, renal compensation
respiratory alkalosis = HCO3- is low
respiratory acidosis = HCO3- is high
82
Disorders of Acid/Base - Effects
Altered neuronal excitablility
CNS changes.
Changes in metabolic activity – enzyme
systems
Changes in K+ concentration – DCT secretion.
If H+ increases K+ falls and vice versa
83
1 kPa =
7.5 mmol/L
84
Treatment of Metabolic Acid/Base Disorders
Metabolic ACIDOSIS
Ideally correct the underlying cause
Infusion of sodium bicarbonate. 1.26% is isotonic.
Strengths up to 8.4% may be used but slow infusion!
85
Treatment of Metabolic Acid/Base Disorders
Metabolic ALKOLOSIS
Correct underlying cause
Infusion of 0.9% sodium chloride - Rehydration
Ammonium Chloride orally – In severe cases
86
Treatment of respiratory Acid/Base Disorders
Respiratory acidosis
Bronchodilators (to reverse airways obstruction)
Antibiotics
Oxygen therapy to reduce hypoxia
Non-invasive positive pressure ventilation
87
Treatment of respiratory Acid/Base Disorders
Respiratory alkalosis
Resolve the underlying cause
Reduce blood CO2
Strategies that may be used: -
Oxygen therapy
Reassurance
Diuretics
Breath holding techniques
Positive end expiratory pressure – to hold the
inspiratory phase a little longer
88
what do you need to know about sample size and mixing
the lrger the sample size, the lower the variability
89
why is powder flow important
weight of powder in the same volume could vary, weight and dose discrepancies
90
Factors Affecting Flow
Particle size
Size distribution
Particle density
Particle shape
Moisture content
Electrostatic charge
91
Frequently used
excipients
Wet binders
(Dry binders)
Lubricants
Disintegrants
Diluents
Coats
92
Sometimes used
excipients
antiadherants
colourants
glidants
93
rarely used
excipients
Wetting agents
Flavours
pH modifiers
94
tell me about target identification
Targets can be DNA, RNA,
Proteins (or membranes)
* Most targets for current drugs
are enzymes or G-protein
coupled receptors (GPCR)
* Most pharmaceuticals are
small molecules but between
2003 and 2006 biologicals
(antibodies, proteins,
enzymes) represented 24%
percent of all new approvals
in the US, and are due to
overtake small molecules by
2020.
95
what is bological screening
Biological screening, also known as bioassay, is a vital step in drug discovery. It involves testing compounds against specific biological assays to identify those with desired activity. The process includes selecting assays, screening compound libraries, analyzing data, confirming hits, and selecting lead compounds for further development. It's a crucial method for identifying potential drugs efficiently.
96
Forward and reverse genetics
Forward genetics starts with a phenotype, inducing mutations to find associated genes, while reverse genetics begins with known genes, modifying them to understand their function. Both approaches aid in understanding gene function and phenotype-genotype relationships.
97
what is genomics
RNA sample prep
sample amplification and labelling PCR
hybridise sampels to chip
array reading and data analysis
98
what is proteomics
protein sample prep
2D seperation, isoelectricfocusing, SDS-PAGE
excise and digest protein
mass spec analysis
99
what is genetic association
selection of candidate genes
detection of SNP
genotyping of DNA
analysis of data
100
what is an SNP
An SNP (Single Nucleotide Polymorphism) is a common type of genetic variation that occurs when a single nucleotide (A, T, C, or G) at a specific position in the genome differs among individuals in a population. SNPs are the most abundant type of genetic variation in humans and are found throughout the genome. They can occur in both coding and non-coding regions of the DNA and can have various effects on traits, susceptibility to diseases, and drug responses. SNPs serve as important genetic markers used in genetic studies to map genes associated with diseases, identify population differences, and understand individual genetic variation.
101
what is a genome
the complete set of sequences in the
genetic material of an organism.
102
how is transcriptome formed
transcription
103
what is a transcriptome
the set of expressed genes, ie genes
transcribed into RNA in a cell at a given point in time
104
what is static
blueprint
High definition data can be collected
105
what is dynamic
but (mostly) not functional
Data can be collected genome-wide
106
how is the proteome formed
translation
107
what is the proteome
the set of proteins including their
modifications expressed in a cell at a given point
in time
108
what is the proteome responsible for
Responsible for functioning of cell
Maximum information - maximum complexity
109
what is the metabolome
function:
endogenous
small molecules present in a cell at a
given point in time
110
what information is possible to collect at high density data
information on enzyme activity and cell statu- is
possible to collect high density data
111
decsribe the information pyramid in the human genome
genes
+transcripts
++ functional entities
112
tell me more about SNPs
When a single base differs between individuals (being A instead of G, for
example)
* A variation must occur in at least 1% of the population to be considered
a SNP.
* SNPs occur about once every 100-300 base pairs along the human
genome, are the bulk of the 3 million variations found in the human
genome, and make up about 90% of all human genetic variation
* The frequency of a particular polymorphism tends to remain stable in the
population.
* Unlike the other, rarer kinds of variations, many SNPs occur in genes
and in the surrounding regions of the genome that control their
expression or some other function.
* The effect of a single SNP on a gene may not be large - perhaps
influencing the activity of the encoded protein in a subtle way - but even
subtle effects can influence susceptibility to common diseases (e.g. E4
of ApoE in Alzheimer’s disease).
* Give information on genetic predisposition, likely response to specific
therapy, prognosis, some specific, some less clear.
* Not the whole story – environmental factors, protective SNPs, epigenetic
information
113
what does genomics do
Can compare genomes from diseases and identify genes that correlate with
disease.
Can correlate model systems (mouse, fly) with human.
The understanding of how this dysfunction changes the phenotype can then
be used to identify potential target genes or gene products for drugs
114
tell me about personalised medicine in genomics
Record individual genome
information, and use this to
predict most effective
treatment (drug, dose, etc) or
likely susceptibility and
predisposition to disease
115
what is transcriptomics
The genome-wide study of mRNA
expression levels
116
tell me whats different from the transcriptome and the genome
The Transcriptome is the set of all mRNA molecules (or
transcripts) in one or a population of biological cells for a given
set of environmental circumstances.
Unlike the genome, which is fixed for a given organism (apart
from genetic polymorphisms), the transcriptome varies
depending upon the context of the experiment.
117
when is the only time genome differs in an organism
genetic polymorphisms
118
what will the next stage of genomic reasearch conduct
will begin to derive
meaningful knowledge from the DNA sequence
119
3 methods for identifying targets
. Screening
* Forward and reverse genetics
* Proteomics and genomics
120
what is proteomics detail
The study of the complete protein complement of a
cell (or sub-fraction thereof e.g. isolated organelle).
Comparison of diseased vs. healthy cells, infectious vs. non-
infectious, etc., and the identification of the proteins
responsible.
More informative than the genome (Drosophila genome 15,000
genes, human genome 22,000 genes, but how many proteins?).
Proteomics
Relies on genome information and integration
of information from a wide variety of sources.
121
how do you seperate proteins in proteomics
Separate proteins by isoelectric point (pI) in first dimension
122
how do you then seperate prtoteins in stage 2 by size
SDS
123
what can you analyse in proteomics
up regulated proteins
down regulated proteins
no change
relate to:
Relate to biochemistry
New targets for
developing assays and
drugs
124
what is biochemistry
Biochemistry is the study of chemical processes within living organisms. It focuses on understanding the structure, function, and interactions of biomolecules like proteins, nucleic acids, carbohydrates, and lipids, as well as the metabolic pathways and signaling networks that govern biological activities.
125
what is chemical proteomics
Many drugs have been
discovered by screening
but their target is often
not known.
Chemical proteomics uses
the drug as a bait to
capture the proteins that
bind to the drug.
The target and off target
proteins can be identified.
126
chemical proteomics example:
trapoxin
a fungal product identified as an anticancer agent, found to bind to
histone deacetylase (HDAC)
* shown to be a HDAC inhibitor – led to an understanding of
epigenetics.
* this led directly to the development of the clinically used HDAC
inhibitors suberoylanilide hydroxamic acid (SAHA) and
Romidepsin (FK228) for the treatment of lymphoma
127
Induced phenotypic approaches
examples 2
ake a model organism
* Mutate it (chemically) and look for disease like phenotypes
* Identify the gene that is changed by sequencing the genome
* Use RNAi to “silence” genes and look for disease like phenotypes
NOTE: RNAi – small double stranded RNA that are put into cells and
produce siRNA (single stranded) that interacts with the cellular
mRNA and prevent the gene product being formed
128
An example from Genomics
The Her2 gene (ErbB, epidermal growth factor receptor family)
was identified as an oncogene in a model using chemically
induced rat neuroblastoma in 1984.
Found to be overexpressed in <25% of breast carcinoma
Köhler and Milstein had discovered the use of antibodies in therapy
in 1975 – approach used to develop Herceptin
Trastuzumab (1988) developed as therapy, approved 2005
129
how much human DNA codes for protein products?
3%
130
Technology can deliver new knowledge and understanding
tell me about it
The general belief is that
around 3% of the human
genomic DNA codes for
protein products
* Evidence from total
transcribed genome analysis
suggested that there may be
a large amount (possibly as
much again) DNA being
transcribed as was
previously predicted.
* Is this meaningful?
* Discovery of micro-RNA
131
what is chemical genetics
Chemical genetics is the use of small molecules to study and manipulate biological systems. It employs these molecules as tools to understand gene function, cellular processes, and disease mechanisms by selectively targeting proteins, enzymes, or signaling pathways within cells.
132
chemical genetics examples
Nothing new – aspirin from willow bark but not until 1970 that target
identified – led to new analgesics
Rapamycin – from Streptomyces hygroscopicus in 1970’s as antifungal
found to inhibit mTOR
Current methods involve screening for a compound that gives a
desired phenotype
* Monastrol identified as antimitotic (from >16,000 compounds)
* Using a screen to look at disruption of H-Ras and Raf1, >73,000
compounds screened and one compound identified – MCP1
133
what does systerms biology and systems medicine do?
While looking at individual targets allows us to develop
specific pharmaceuticals, it is common for resistance to
develop or of-target effects to become apparent after time.
Systems biology and systems medicine aim to look at a whole
biological system, and to develop functional models that allow
us to predict the effects of changing one component – e.g.
targeting one protein.
Also aim to develop systems wide screens for identifying
biomarker patterns that can be used in diagnosis and
monitoring of treatmen
134
what is target identification
Identifying cellular components that could be targets for developing
new drugs
* Identifying the cellular targets (and off-target effects) of current drugs
and new chemical entities (NCE)
* Identifying appropriate therapeutic doses
* Identifying likely efficacy of treatments
* Identifying combination therapies that prevent or circumvent
resistance.
135
4 mrthods of arget identification
High-content (or other) screening
Clinical screening
Molecular biochemical understanding of phenotype
Systems biology and systems medicine
136
Sites of action of anti-bacterial agents
where do B-lactams act?
act at bacterial cell wall synthesis
137
Sites of action of anti-bacterial agents
where do glycopeptides act
act at bacterial cell wall synthesis
138
Sites of action of anti-bacterial agents
ribosome protein synthesis
ribosome give some drug class examples
macrolides
azalidesazalides
lincosamides
oxazolidinones
chloramphenicol
tetracyclines
aminoglycosides
mupirocin
fusidic acid
pleuromutilins
139
site of action of anti bacterial agents
chromosome DNA replication
give some drug class examples
quinolines
rifampicin
nitroimidazoles
nitrofurans
140
site of action of antibacterial agents
metabolism
give some examples
antifolates
sulphonamides
trimethoprim
141
site of action of antibacterial agents
cell membrane disruption
give some examples
polymyxins
daptomycin
142
main antibacterial agents
B-lactams
examples
penicillins, cephalosporins, carbapenems,
monobactams, clavulanic acid, sulbactam,
tazobactam
143
main antibacterial agents
glycopeptides
examples
vancomycin, teicoplanin
144
[Others that act as anti-mycobacterial (TB) agents:
antibacterials
cycloserine (target: peptidoglycan)
isoniazid (target: mycolic acids)
ethambutol (target: arabinogalactan)]
145
Gram Negative
cell wall structure
bacteria
1-inner membrane
2-periplasmic space
3-outer membrane
4-phospolipid
5-peptidoglycan
6 li i6-lipoprotein
7-protein
8-Lipopolysaccharide
9 porins9-porin
146
gram positive
cell wall structure
bacteria
1 cytoplasmic membrane
2-peptidoglycan
3-phospholipid
4-protein
147
General bacterial cell wall structure
-lactam and glycopeptide antibiotics inhibit synthesis
of the peptidoglycan component of the bacterial cell
wall.
* Peptidoglycan is essential to nearly all bacteriaPeptidoglycan is essential to nearly all bacteria
* Peptidoglycan is unique to bacterial cell walls, no
related polymer is found in mammalian cells
148
what does transpeptidase do
Removes terminal D-alanine and cross-
links the peptides
with pentaglycine
149
what type of peptidoglycan is in gram negative becteria
Escherichia coli
peptidoglycan
150
what type of peptidoglycan is in gram positive bacteria
Staphylococcus aureus
peptidoglycan
151
structures of penecillin G
B-lactam antibiotics
fermentation of penicillin with phenylacetic acid
152
structure of penicillin V
B-lactam antibiotics
fermentation of penicillin with phenoxyacetic acid
153
what is the function of TPase/transpeptida
The function of transpeptidase (TPase), also known as penicillin-binding proteins (PBPs) in bacteria, is to catalyze the final step in the synthesis of peptidoglycan, a key component of the bacterial cell wall. Transpeptidase enzymes are responsible for crosslinking the peptide chains of adjacent glycan strands in the peptidoglycan layer, providing structural integrity and strength to the bacterial cell wall.
they are a catalyst
154
Penicillin inhibition of transpeptidase
penicillin inhibits transpeptidase, also known as penicillin-binding proteins (PBPs), through a mechanism involving its beta-lactam ring structure.
enicillin binds to transpeptidase, inhibiting its activity by forming a stable complex.
This prevents crosslink formation in the peptidoglycan layer, weakening the cell wall.
Ultimately, this disruption leads to bacterial cell death, particularly affecting actively growing bacteria.
155
MOA of penecillin
Binding to Transpeptidase: Penicillin molecules are structurally similar to the D-alanyl-D-alanine dipeptide, a substrate for transpeptidase. Penicillin binds to the active site of transpeptidase, mimicking the structure of the substrate.
Inhibition of Transpeptidase Activity: Once bound to transpeptidase, penicillin irreversibly inhibits the enzyme's activity by covalently attaching to the serine residue within the active site. This forms a stable penicilloyl-enzyme complex, preventing transpeptidase from catalyzing the formation of crosslinks in the peptidoglycan layer.
Disruption of Cell Wall Synthesis: As a result of transpeptidase inhibition, the formation of crosslinks between peptide chains in the peptidoglycan layer is blocked. Without proper crosslinking, the integrity of the bacterial cell wall is compromised, leading to cell wall weakening and eventual cell lysis.
Bactericidal Effect: By disrupting cell wall synthesis, penicillin ultimately causes bacterial cell death. The bactericidal effect of penicillin is particularly effective against actively growing bacteria, as they rely heavily on cell wall synthesis for cell division and growth. shorten bullet points
156
Development of semi-synthetic penicillins
While PenV and PenG were the first effective penicillins, they have
limitations – better penicillns were needed but hard to synthesize.
* When starved of phenylacetic acid, Penicillium chrysogenum produces thep y , y g p
penicillin nucleus, 6-aminopenicillanic acid (6-APA).
* 6-APA has little intrinsic activity
* 6-APA can be converted to an active penicillin by reaction with anp y
activated acid (e.g. acyl chloride)
157
what is intrinsic activity
The term intrinsic activity refers to the maximal possible effect that can be produced by a drug. Intrinsic activity is determined by the drug-receptor relationship for a drug that acts on receptors.
158
what is a semi synthetic penecillin
The semisynthetic penicillins are prepared by modifying the acyl side chain (See Figure 1). There are five categories of semisynthetic penicillins: antistaphylococcal penicillins, aminopenicillins, car- boxypenicillins, ureidopenicillins, and ß-lactamase-resistant penicil- lins.
159
what are the benefits of a semi synthtic penecillin
The fourth generation penicillins are semisynthetic modifications of natural penicillin that have the advantage of an extended spectrum of activity particularly against gram negative bacteria including Pseudomonas, Enterobacter, Proteus and Klebsiella species
160
tell me about flucoxacillin
Good against
resistant Gram
+ve e.g. MRSA
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tell me about amoxycillin
medium spectrum
good against gram +ve
and some gram-ve
162
give me an example of a broad spectrum semi synthetic penicillin
piperacillin
163
tell me about the hydrolysis of penecillin by B lactamase
B lactamase speeds up hydrolysis as it is an enzyme (catalyst)
B lactamase has nucelophillic serine group that attacks amine group on penecillin
chages the structure of the enzyme slightly in the intermediate to allow water to interact with the active site
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give examples of Blactamase inhibitors
Clavulanic acid, amoxicillin
Sulbactam, ampicillin
Tazobactam, piperacillin
165
tell me the MOA of B lactamase inhibitors
B lactamase nucleophile attacks the B lactamase inhibitor at B lactam ring
two stable intermediates formed
stable acyl enzyme
stable crosslinked acyl enzyme
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Cephalosporins, what are they
Cephalosporins (cephems) are another class of -lactam
antibiotic
Cephalosporin C is a naturally produced antibiotic (by the* Cephalosporin C is a naturally produced antibiotic (by the
fungus Acremonium)
* CephC can be chemically modified to a range of semi-
s nthetic cephalosporinssynthetic cephalosporin
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Cephalosporins and similarity to penecillines
both have B lactam rings
168
differences between cephalosporins and penecillins
6 membered ring attached to b lactam ring
penecillin had 5 membered ring attached to 4 membered B lactam ring
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what can cephalosporins do
treat organisms resistant to penecillin
thats how it was discovered
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Semisynthetic cephalosporins
tell me about them
Cephalospin C limited clinical stability
S i th ti h l i ( h l ti* Semisynthetic chepalosporins (e.g. cephalotin,
1964) were produced to improve stability
– 1 st generation cephalosporins
* 2 nd generation broader spectrum – more Gram
negative activity.
* Now on 5 th generation! (e.g.Ceftobiprole,
Ceftaroline).
* 4 th and 5 th generation very broad spectrum.
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what is a carbapenem drug example
Thienamycin
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what do carbapenems do
Thienamycin is a naturally produced carbapenem
antibiotic (Streptomyces) – most potent to date
B d t (G d G ) d i t t* Broad spectrum (G +ve and G ‐ve) and resistant
to β‐lactamase
* Can be chemically modified to a range of semi‐synthetic carbapenems
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give me an example of a sensitive to renal peptidase, carbapenem
Imipenem
used with cilastatin
174
give me an example of a resistant to renal peptidase, carbapenem
meropenem IV
175
what is a monobactam
B lactam antibiotic
Often tolerated by patients who have
hypersensitivity to penicillins
176
what is a naturally produced monobactam
Nocardicin A is a naturally produced
monobactam b‐lactam antibioticmonobactam b‐lactam antibiotic
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what is a synthetically produced B lactam
Aztreonam is a synthetic monobactam,
resistant to b‐lactamases and is the only
clinically used monobactam
IV / inhlation
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Adverse Drug Reaction in penecillin
Mild” adverse drug reaction (ADR) (hypersensitivity) to
penicillins occur in about 1% of patients (diarrhea, nausea, rash,
)…)
* 10% tend to report some of these effects but these are often
not related to the penicillin
Thi i t I (I E)* This is a type I response (IgE)
* Believed to be due to “haptenization” of proteins
Cross‐sensitivity is low between classesy
* Severe anaphylaxis occurs in around 0.01%. Mechanism unclear.
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Glycopeptide antibiotics
example
vancomycin
Vancomycin is a naturally produced glycopeptide
antibiotic (initially isolated from Nocardia orientalis)
* Now produced by fermentation
* Biosynthesis by unusual non-
ribosomal peptide synthesis
* Effective against Gram +ve bacteria
non B lactam antibiotic
no 4 membered ring
good for treating B lactam resistant organisms
has both sugar and peptide chain (NA/=O): how to identify via structure
180
what is another example of a glycopeptide antibiotic that isnt vancomycin
Teicoplanin
Teicoplanin is another example of a naturally produced glycopeptide antibiotic
(from Actinoplanes teichomyceticus)
* Teicoplanin is a mixture of (at least) 5 compounds with the same glycopeptide
core
181
disadvantage of teicoplanin
mixture of 5 compunds
as produced naturally again, hard to tell what % of each varied compound is in drug
182
MOA vancomycin
When it reaches the cell wall of an actively dividing susceptible gram-positive bacterium, vancomycin binds to the acyl-D-ala-D-ala portion of the growing cell wall. After binding, it prevents the cell wall from forming the cross-linking necessary to keep it strong
Glycopeptide antibiotics block formation of the peptidoglycan in two ways:
* preventing the formation of the linear glycan (NAG-NAM) strands by
transglycosylase
* inhibiting peptide cross linking by transpeptidase
* They do this by binding tightly to the terminal D-alanyl-D-alanine of the
peptidoglycan by hydrogen bonding.
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