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week 18 (Y2) > the medicine > Flashcards

the medicine Flashcards

1
Q

what is the definition of a bacteria

A

Prokaryotic organism (no nucleus).

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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

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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

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4
Q

what are Protozoa (protists)

A

Non-photosynthetic
unicellular organisms with protoplasm
differentiated into nucleus and cytoplasm

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5
Q

what are fungi

A

non-photosynthetic organisms that
possess relatively rigid cell walls (chitin).

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6
Q

what is a virus

A

infects other cells and requires host cell
machinery to replicate

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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)

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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

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9
Q

name a narrow spectrum abs

A

vancomycin

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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.
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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.
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12
Q

list indications for naproxen

A

Naproxen - Upset stomach, ulcer, nausea, heartburn, headache, drowsiness, dizziness

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13
Q

list indications for omeprazole

A

Omeprazole - diarrhoea, nausea, constipation, abdominal pain, vomiting, headache,
susceptibility to C. difficile

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14
Q

who is Paul Ehrlich (1854-1915)

A

“Magic Bullet” (arsphenamine
for the treatment of syphilis)

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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

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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

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17
Q

what is H2CO3

A

carbonic acid

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18
Q

what is the normal pH value

A

7.35

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19
Q

give an example of a volatile acid

A

carbon dioxide

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20
Q

give examples of a non volatile acid

A

Metabolic Acids e.g. Lactic acid, keto acids, uric
acid

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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

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22
Q

Extracellular Fluid

A

Carbonic Acid Buffer

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23
Q

Intracellular Buffer

A

Proteins
Blood Stream: Haemoglobin Buffer

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24
Q

physiological buffers in
Renal Tubule

A

Phosphate & Ammonia

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25
Q

what can a buffer system not do

A

buffer itself

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26
Q

what is a Bronsted-Lowry acid

A

acid a substance capable of donating
a proton;

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27
Q

what is a lewis acid

A

electron acceptor

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28
Q

what is a Bronsted-Lowry base

A

base a substance capable of accepting a proton

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29
Q

what is aa lewis base

A

electron donor

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30
Q

strength of an acid is measured by

A

Strength of an acid is measured by the ability to donate protons
Water is an amphiprotic solvent: can accept and donate protons

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31
Q

H2PO4- is termed as?

A

titratable acidity

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32
Q

what are protons buffered by

A

histidine residues

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33
Q

explain haemoglobin blood buffers

A

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.

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34
Q

explain the ideal buffer

A

equal concs of acid and base

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35
Q

what % do Central Chemoreceptors drive

A

70-80%

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36
Q

what % do Peripheral Chemoreceptors drive

A

20-30%

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37
Q

describe renal regulation of pH

A

Reabsorption of bicarbonate HCO3-
Secretion of protons
Facilitated by Carbonic Anhydrase

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38
Q

tell me about tubular buffers bicarbonate

A

filtered, normally fully
reabsorbed in PCT

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39
Q

tell me about tubular buffers phosphate

A

filtered, major buffer in the
DCT

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40
Q

tell me about tubular buffers ammonia

A

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

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41
Q

pH referance range

A

pH = 7.35 – 7.45

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42
Q

PaCO2 referance range

A

PaCO2 = 4.7 – 6.0kPa
(35 - 45 mmHg)

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43
Q

PaO2 referance range

A

PaO2 = 10 – 13kPa
(70 – 100 mmHg)

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44
Q

HCO3- refernace range

A

[HCO3-] = 22 – 26mmol/L

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45
Q

SaO2 referance range

A

SaO2 = 96 – 98% (in adults)

Sa = saturation
expressed as a %

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46
Q

what is Acidosis

A

pH falls below 7.35
so, increasing H+ from either too much pCO2 or
too little HCO3-

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47
Q

what is Alkalosis

A

pH rises above 7.45
vice-versa, i.e. decreasing H+ from reduced
PCO2 or increased HCO3-

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48
Q

PaCO2 = Partial pressure of carbon dioxide

A

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

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49
Q

PaO2 = Partial pressure of oxygen - is

A

is the amount of
oxygen dissolved in the blood and represents gas
exchange in the blood.

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50
Q

SaO2 = Oxygen saturation

A

ratio of oxygen bound to
haemoglobin.

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51
Q

what is pH

A

determines the concentration of hydrogens found in
arterial blood.

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52
Q

HCO3- Bicarbonate is

A

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

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53
Q

what is Base excess

A

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.

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54
Q

what is Metabolic Disorder

A

Involves non-volatile acid or altered HCO3-

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55
Q

what is Respiratory Disorder

A

Primary change is in plasma CO2 (Volatile Acid)

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56
Q

what is Plasma Buffers disorder

A

more effective in acidosis
than alkalosis

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57
Q

Decreased Acid Secretion cause of acidosis

A

Renal Failure
Type 1 Renal Tubular Acidosis (DCT)
Hypoaldosteronism (Type 4 renal tubular
acidosis)

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58
Q

Increased Metabolic Acid Production cause of acidosis

A

Lactic acidosis
Ketoacidosis –uncontrolled diabetes mellitus
Ingestion of Acidic material e.g. aspirin

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59
Q

Loss of Bicarbonate cause of acidoisis

A

Diarrhoea and loss of intestinal bicarbonate
Type 2 renal tubular acidosis (PCT)

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60
Q

Metabolic Acidosis tell me about it

A

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

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61
Q

Gastrointestinal Hydrogen Loss cause of alkalosis

A

Loss of gastric secretion – e.g. vomiting

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62
Q

Urinary Loss of Hydrogen cause of alkalosis

A

Loop or Thiazide Diuretics
Hyperaldosteronism

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63
Q

Movement of H+ into Cells cause of alkalosis

A

Hypokalaemia

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64
Q

causes of metabolic alkolosis

A

Administration of Bicarbonate or an
organic ion metabolised to Bicarbonate
(e.g. citrate)

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65
Q

tell me more about metabolic alkolosis

A

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

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66
Q

respiratory acidosis causes

A

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

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67
Q

what are three types of mixing

A

random, ordered and perfect mix

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68
Q

consequenses of respiratory acidosis

A

ACUTE
HYPERCAPNIA

renal compensation leads to

CHRONIC HYPERCAPNIA

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69
Q

tell me about respiratory alkolosis when renal compensation occurs

A

Renal Compensation: reduced H+ excretion and
bicarbonate reabsorption

At full compensation both buffer components are
depressed and there is positive base excess

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70
Q

Respiratory Alkalosis - causes

A

Causes – Central nervous system
Head injury
Cardiovascular accident (CVA)
Anxiety (hyperventilation syndrome)
Supra-tentorial (e.g. pain, fear, stress)
Pyrexia
Chronic liver failure

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71
Q

respiratory acidosis signs and symptons

A

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.

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72
Q

respiratory alkolosis signs and symptoms

A

Breathlessness.
Dizziness.
Numbness and /or tingling in your fingertips, toes and lips.
Irritability.
Nausea.
Muscle spasms or twitching.
Fatigue.
Dizziness/lightheadedness.

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73
Q

what happens when CO2 is high

A

< 7.35
acidosis
respiratory acidosis

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74
Q

what happens when HCO3- is low

A

bicarbonate
< 7.35
acidosis
metabolic acidosis

75
Q

what happens when CO2 is low

A

> 7.35
alkalosis
respiratory alkalosis

76
Q

what happens when HCO3- is high

A

Bicarbonate
> 7.35
alkalosis
metabolic alkalosis

77
Q

normal value for PaO2

A

> 10.6 kPa

78
Q

normal value for PaCO2

A

4.6 - 6.0 kPa

79
Q

normal HCO3 values

A

22 - 28 mmol/L

80
Q

when does respirtatory compensation occur

A

metabolic alkolisos = co2 is high
metabolic acidosis = co2 is low

81
Q

when does metabolic compensation occur, renal compensation

A

respiratory alkalosis = HCO3- is low
respiratory acidosis = HCO3- is high

82
Q

Disorders of Acid/Base - Effects

A

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
Q

1 kPa =

A

7.5 mmol/L

84
Q

Treatment of Metabolic Acid/Base Disorders
Metabolic ACIDOSIS

A

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
Q

Treatment of Metabolic Acid/Base Disorders
Metabolic ALKOLOSIS

A

Correct underlying cause
Infusion of 0.9% sodium chloride - Rehydration
Ammonium Chloride orally – In severe cases

86
Q

Treatment of respiratory Acid/Base Disorders
Respiratory acidosis

A

Bronchodilators (to reverse airways obstruction)
Antibiotics
Oxygen therapy to reduce hypoxia
Non-invasive positive pressure ventilation

87
Q

Treatment of respiratory Acid/Base Disorders
Respiratory alkalosis

A

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
Q

what do you need to know about sample size and mixing

A

the lrger the sample size, the lower the variability

89
Q

why is powder flow important

A

weight of powder in the same volume could vary, weight and dose discrepancies

90
Q

Factors Affecting Flow

A

Particle size
Size distribution
Particle density
Particle shape
Moisture content
Electrostatic charge

91
Q

Frequently used
excipients

A

Wet binders
(Dry binders)
Lubricants
Disintegrants
Diluents
Coats

92
Q

Sometimes used
excipients

A

antiadherants
colourants
glidants

93
Q

rarely used
excipients

A

Wetting agents
Flavours
pH modifiers

94
Q

tell me about target identification

A

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
Q

what is bological screening

A

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
Q

Forward and reverse genetics

A

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
Q

what is genomics

A

RNA sample prep
sample amplification and labelling PCR
hybridise sampels to chip
array reading and data analysis

98
Q

what is proteomics

A

protein sample prep
2D seperation, isoelectricfocusing, SDS-PAGE
excise and digest protein
mass spec analysis

99
Q

what is genetic association

A

selection of candidate genes
detection of SNP
genotyping of DNA
analysis of data

100
Q

what is an SNP

A

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
Q

what is a genome

A

the complete set of sequences in the
genetic material of an organism.

102
Q

how is transcriptome formed

A

transcription

103
Q

what is a transcriptome

A

the set of expressed genes, ie genes
transcribed into RNA in a cell at a given point in time

104
Q

what is static

A

blueprint
High definition data can be collected

105
Q

what is dynamic

A

but (mostly) not functional
Data can be collected genome-wide

106
Q

how is the proteome formed

A

translation

107
Q

what is the proteome

A

the set of proteins including their
modifications expressed in a cell at a given point
in time

108
Q

what is the proteome responsible for

A

Responsible for functioning of cell
Maximum information - maximum complexity

109
Q

what is the metabolome

A

function:

endogenous
small molecules present in a cell at a
given point in time

110
Q

what information is possible to collect at high density data

A

information on enzyme activity and cell statu- is
possible to collect high density data

111
Q

decsribe the information pyramid in the human genome

A

genes
+transcripts
++ functional entities

112
Q

tell me more about SNPs

A

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
Q

what does genomics do

A

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
Q

tell me about personalised medicine in genomics

A

Record individual genome
information, and use this to
predict most effective
treatment (drug, dose, etc) or
likely susceptibility and
predisposition to disease

115
Q

what is transcriptomics

A

The genome-wide study of mRNA
expression levels

116
Q

tell me whats different from the transcriptome and the genome

A

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
Q

when is the only time genome differs in an organism

A

genetic polymorphisms

118
Q

what will the next stage of genomic reasearch conduct

A

will begin to derive
meaningful knowledge from the DNA sequence

119
Q

3 methods for identifying targets

A

. Screening
* Forward and reverse genetics
* Proteomics and genomics

120
Q

what is proteomics detail

A

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
Q

how do you seperate proteins in proteomics

A

Separate proteins by isoelectric point (pI) in first dimension

122
Q

how do you then seperate prtoteins in stage 2 by size

A

SDS

123
Q

what can you analyse in proteomics

A

up regulated proteins
down regulated proteins
no change

relate to:
Relate to biochemistry
New targets for
developing assays and
drugs

124
Q

what is biochemistry

A

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
Q

what is chemical proteomics

A

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
Q

chemical proteomics example:
trapoxin

A

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
Q

Induced phenotypic approaches
examples 2

A

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
Q

An example from Genomics

A

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
Q

how much human DNA codes for protein products?

A

3%

130
Q

Technology can deliver new knowledge and understanding

tell me about it

A

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
Q

what is chemical genetics

A

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
Q

chemical genetics examples

A

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
Q

what does systerms biology and systems medicine do?

A

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
Q

what is target identification

A

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
Q

4 mrthods of arget identification

A

High-content (or other) screening
Clinical screening
Molecular biochemical understanding of phenotype
Systems biology and systems medicine

136
Q

Sites of action of anti-bacterial agents
where do B-lactams act?

A

act at bacterial cell wall synthesis

137
Q

Sites of action of anti-bacterial agents
where do glycopeptides act

A

act at bacterial cell wall synthesis

138
Q

Sites of action of anti-bacterial agents
ribosome protein synthesis
ribosome give some drug class examples

A

macrolides
azalidesazalides
lincosamides
oxazolidinones
chloramphenicol
tetracyclines
aminoglycosides
mupirocin
fusidic acid
pleuromutilins

139
Q

site of action of anti bacterial agents
chromosome DNA replication
give some drug class examples

A

quinolines
rifampicin
nitroimidazoles
nitrofurans

140
Q

site of action of antibacterial agents
metabolism
give some examples

A

antifolates
sulphonamides
trimethoprim

141
Q

site of action of antibacterial agents
cell membrane disruption
give some examples

A

polymyxins
daptomycin

142
Q

main antibacterial agents
B-lactams
examples

A

penicillins, cephalosporins, carbapenems,
monobactams, clavulanic acid, sulbactam,
tazobactam

143
Q

main antibacterial agents
glycopeptides
examples

A

vancomycin, teicoplanin

144
Q

[Others that act as anti-mycobacterial (TB) agents:
antibacterials

A

cycloserine (target: peptidoglycan)
isoniazid (target: mycolic acids)
ethambutol (target: arabinogalactan)]

145
Q

Gram Negative
cell wall structure
bacteria

A

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
Q

gram positive
cell wall structure
bacteria

A

1 cytoplasmic membrane
2-peptidoglycan
3-phospholipid
4-protein

147
Q

General bacterial cell wall structure

A

-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
Q

what does transpeptidase do

A

Removes terminal D-alanine and cross-
links the peptides
with pentaglycine

149
Q

what type of peptidoglycan is in gram negative becteria

A

Escherichia coli
peptidoglycan

150
Q

what type of peptidoglycan is in gram positive bacteria

A

Staphylococcus aureus
peptidoglycan

151
Q

structures of penecillin G
B-lactam antibiotics

A

fermentation of penicillin with phenylacetic acid

152
Q

structure of penicillin V
B-lactam antibiotics

A

fermentation of penicillin with phenoxyacetic acid

153
Q

what is the function of TPase/transpeptida

A

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
Q

Penicillin inhibition of transpeptidase

A

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
Q

MOA of penecillin

A

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
Q

Development of semi-synthetic penicillins

A

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
Q

what is intrinsic activity

A

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
Q

what is a semi synthetic penecillin

A

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
Q

what are the benefits of a semi synthtic penecillin

A

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
Q

tell me about flucoxacillin

A

Good against
resistant Gram
+ve e.g. MRSA

161
Q

tell me about amoxycillin

A

medium spectrum
good against gram +ve
and some gram-ve

162
Q

give me an example of a broad spectrum semi synthetic penicillin

A

piperacillin

163
Q

tell me about the hydrolysis of penecillin by B lactamase

A

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

164
Q

give examples of Blactamase inhibitors

A

Clavulanic acid, amoxicillin

Sulbactam, ampicillin

Tazobactam, piperacillin

165
Q

tell me the MOA of B lactamase inhibitors

A

B lactamase nucleophile attacks the B lactamase inhibitor at B lactam ring

two stable intermediates formed

stable acyl enzyme
stable crosslinked acyl enzyme

166
Q

Cephalosporins, what are they

A

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

167
Q

Cephalosporins and similarity to penecillines

A

both have B lactam rings

168
Q

differences between cephalosporins and penecillins

A

6 membered ring attached to b lactam ring
penecillin had 5 membered ring attached to 4 membered B lactam ring

169
Q

what can cephalosporins do

A

treat organisms resistant to penecillin
thats how it was discovered

170
Q

Semisynthetic cephalosporins
tell me about them

A

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.

171
Q

what is a carbapenem drug example

A

Thienamycin

172
Q

what do carbapenems do

A

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

173
Q

give me an example of a sensitive to renal peptidase, carbapenem

A

Imipenem
used with cilastatin

174
Q

give me an example of a resistant to renal peptidase, carbapenem

A

meropenem IV

175
Q

what is a monobactam

A

B lactam antibiotic

Often tolerated by patients who have
hypersensitivity to penicillins

176
Q

what is a naturally produced monobactam

A

Nocardicin A is a naturally produced
monobactam b‐lactam antibioticmonobactam b‐lactam antibiotic

177
Q

what is a synthetically produced B lactam

A

Aztreonam is a synthetic monobactam,
resistant to b‐lactamases and is the only
clinically used monobactam

IV / inhlation

178
Q

Adverse Drug Reaction in penecillin

A

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.

179
Q

Glycopeptide antibiotics
example

A

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
Q

what is another example of a glycopeptide antibiotic that isnt vancomycin

A

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
Q

disadvantage of teicoplanin

A

mixture of 5 compunds

as produced naturally again, hard to tell what % of each varied compound is in drug

182
Q

MOA vancomycin

A

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.

183
Q
A

week 18 (Y2) (3 decks)

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