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MD3001 > Week 10 > Flashcards

Week 10 Flashcards

1
Q

Difference between volume and capacity?

A

Capacity is the sum of more than one volume

Volume cannot be subdivided

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2
Q

What is the measure of airflow obstruction?

What is it’s normal value?

A

FEV1.0/FVC ratio

Normal > 0.7

[This is the percentage of the vital capacity which is expired in the first second of maximal expiration.
FEV1.0= Forced expiratory volume 1.0 measures how much air a person can exhale during a forced breath in the first second
FVC= Forced vital capacity is the total amount of air exhaled during the FEV test.]

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3
Q

Difference between obstructive and restrictive lung disease?

A

Obstructive: Increasing in resting volume due to loss of lung elastic recoil

Restrictive: People with restrictive lung disease cannot fully fill their lungs with air. Their lungs are restricted from fully expanding.

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4
Q 
Difference in following patterns between obstructive and restrictive lung disease?
FVC 
FEV1 
FEF25-75 
MVV
FRC
RV
TLC
A 
Obstructive:
FVC - Same/Decrease
FEV1 - Decrease
FEF25-75 - Decrease
MVV- Decrease
FRC- Increase
RV- Increase
TLC- Increase
Restrictive:
FVC- Decrease 
FEV1 - Same/decrease 
FEF25-75- Same/decrease
MVV- Same/decrease
FRC- Decrease
RV- Decrease
TLC- Decrease
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5
Q 
Define following measurements:
FVC?
FEV1 ? 
FEF 25-75?
MVV?
FRC?
RV?
TLC?
A

FVC: Forced vital capacity is the total amount of air exhaled
FEV1: Forced expiratory volume in the first second
FEF25-75 = Forced Expiratory Flow at 25-75% of FVC
MVV: Maximum Voluntary Ventilation
FRC: Functional Residual Volume, the lung volume at the end of a normal expiration, when the muscles of respiration are completely relaxed
RV: Residual volume, the volume of the lungs after a maximal expiration– the lowest voluntary volume attainable.
TLC: Total lung capacity

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6
Q

In obstructive lung disease:

  • Airflow obstruction measure?
  • Common diseases?
A

FEV1.0/FVC < 0.7

Common disease: Asthma, COPD

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7
Q

What is the clinical presentation of asthma?

A

It is a clinical diagnosis. More than one of the following:

  • Wheeze
  • Breathlessness
  • Chest tightness
  • Cough

Especially if diurnal variation in symptoms and history of atopy.
Hyper-responsive to allergens, exercise, cold air

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8
Q

Define asthma

A

A chronic inflammatory disorder of the airways in susceptible individuals, inflammatory symptoms are usually associated with widespread but variable airflow obstruction and an increase in airway response to a variety of stimuli. Obstruction is often reversible, either spontaneously or with treatment

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9
Q

Effect of airway obstruction on FEV1?

A

Lower FEV1 as the percentage of vital capacity exhaled is lower due to lower rate

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10
Q

What are the three components of the pathophysiology of asthma?

A
  1. Airway narrowing/obstruction
  2. Airway hyper-responsiveness
  3. Airway inflammation (eosinophils)
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11
Q

What are the pathological change sin the airways in asthma?

A
  1. Cellular infiltration
  2. Oedematous submucosa
  3. Thickened BM
  4. Smooth muscle hypertrophy and hyperplasia
  5. Mucous plug
  6. Hyperplasia of mucous glands
  7. Desquamation of epithelium
  8. Neovascularisation
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12
Q

What is an example of non-pharmacological treatment of asthma?

A

SIGN. Shown to:

  1. Achieve and maintain a normal BM if overweight
  2. Breathing exercise programmes
  3. Stop smoking
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13
Q

What is the structure of the pharmacological treatment of asthma?

A
  1. Mild intermittent asthma: Inhaled short-acting B2 agonist as required
  2. Regular preventer therapy: Add dose of corticosteroid per day
  3. Initial add-on therapy: Add inhaled long acting B2 agonist (LABA) –> Assess control of asthma (good response to LABA).
    Benefit from LABA but still poor control = Continue LABA and increase inhaled corticosteroid dose to 800mg/day
    No response to LABA = Stop LABA and increase corticosteroid to 800mg/at
  4. Persistent poor control: Consider further increase of corticosteroid or addition of 4th drug (e.g. leukotriene receptor antagonist)
  5. Continuous or frequent use of oral steroids: Use of daily steroid tablet or refer patient for specialist care
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14
Q

What is COPD?

A

Preventable and treatable
Characterised by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles/gases

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15
Q

Causes of COPD

A
  1. TOBACCO SMOKING
  2. Indoor/outdoor pollution from biomass fuels
  3. alpha-1 antitypsin deficiency
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16
Q

Pathophysiology of COPD

A
  1. Inflammation and fibrosis of the bronchial wall
  2. Hypertrophy of the submucosal glands an hypersecretion of mucous
  3. Loss of elastic, parenchymal lung fibres which hold airway open –> emphysema
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17
Q

Clinical presentation of COPD?

A 
Usually 50s and 60s
Chronic cough
Sputum production
Increased dyspnoea 
Decreasing exercise tolerance
History of exposure to risk factors
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18
Q

Difference between pink puffer and blue bloater presentaiton?

A

Pink puffer:

  • Pink
  • Pursed lips as alveoli tend to collapse
  • Barrel chest due to air trapping
  • Use of accessory muscles
  • Decrease breath sounds

Blue bloater:

  • Blue = cyanosed
  • Bloater = signs of RHF
  • Not just a lung disease (Weight loss, CVS disease, depression, osteoporosis)
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19
Q

Describe the different management strategies for different levels of COPD:

  1. Breathlessness and exercise limitations
  2. Exacerbations or persistent breathlessness
  3. Persistent exacerbations or breathlessness
A
  1. Breathlessness and exercise limitations
    - SABA or SAMA (Short acting muscarinic agonist)
2. Exacerbations or persistent breathlessness
[for FEV>50%]
-LABA
-LAMA (+discontinue SAMA)
[for FEV< 50%]
-LABA and ICS in a combination inhaler
-LAMA (+ discontinue SMA)
  1. Persistent exacerbations or breathlessness
    - LAMA + LABA + ICS in a combo inhaler

ICS= inhaled corticosteroids

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20
Q

What is domiciliary oxygen therapy? Who is it for?

A

Non-invasive positive pressure ventilation

Patients with PaCo2 <8 kPa
Must have stopped smoking
Must be breated for > 15hrs/day for improve mortaility

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21
Q

Describe the main types of research studies employed in medical research

A

Observational studies

  • Case control
  • Cohort
  • Cross sectional

Experimental studies
-Randomised and non-randomised trials

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22
Q

Describe the advantages and disadvantages of case study, series or report

A

Advantages- Quick, cheap, rapid publication, early indicators of problems, can help detects new drug side effects and potential uses
Disadvantages- Statistically weak, no control group, very small numbers of patients, cases may not be generalizable to the wider population

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23
Q

What are the advantages and disadvantages of cross sectional surveys?

A

Advantages- Cheap, simple, ethically café, useful for planning surposes
Disadvantages- Cause/effect, volunteer bias, unequal distribution of confounders

Usually descriptive studies which may show an association between exposure and outcome

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24
Q

Complications of cross sectional surveys?

A

Confounders: Uncontrolled extraneous variables

Spurious association: e.g. Is ultrasound harmful to fetus? Varying conclusions

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25
Q

What are the advantages and disadvantages of case controls studys?

A

Advantages:

  • Simultaneously look at multiple risk factors
  • Good for studying rare conditions
  • Useful as initial studies to establish an association

Disadvantages:

  • Retrospective study which relies on patient recall to determine exposure (recall bias) or patient records
  • Confounders
  • Selection of control group is difficult

The outcome has already occurred and data on exposure is collected from medical records or the administration of questionnaires

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26
Q

Advantages and disadvantages of cohort studies?

A

Advantages:

  • Ethically safe
  • Subjects can be matched
  • Can show cause precedes that effect
  • Easier and cheaper than a RCT

Disadvantages

  • High drop out rate
  • Exposure may be linked to hidden confounder
  • Blinding is difficult
  • Outcome of interest may take a long time to occur
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27
Q

Advantages and disadvantages of cohort studies?

A

Advantages:

  • Ethically safe
  • Subjects can be matched
  • Can show cause precedes that effect
  • Easier and cheaper than a RCT

Disadvantages

  • High drop out rate
  • Exposure may be linked to hidden confounder
  • Blinding is difficult
  • Outcome of interest may take a long time to occur

Outcome has not occurred at the start of the investigation

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28
Q

What is the double blind method?

A

Neither subjects or investigators aware

are of which treatment the subject receives

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29
Q

What are the different design modifiers?

A

Single blind: Subjects did not know which treatment they were receiving

Double blind: Neither subjects or investigators awareof which treatment subject receives

Crossover: Each subject received both the intervention and control treatment (randomly) often separated by a washout period

Placebo control: Control subjects receive placebo (inactive pill, sham operation)

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30
Q

Advantages and disadvantages of RCT?

A

Advantages:

  • Unbiased distribution of confounders
  • Clearly identified population
  • Randomisation help statistical analysis
  • More likely to be ‘blinded’

Disadvantages:

  • Expensive
  • Volunteer bias
  • Ethical issues
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31
Q

What are the different design features of clinical research?

A

Parallel group comparison: Each group receives a different treatment

Paired (matched) comparison: Subjects are matched to balance confounders such as age and sex

Within subject comparison: Subjects assessed before and after an intervention

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32
Q

What are the problems associated with RCTs?

A
  1. Impossible where disease is too rare
  2. Unnecessary when a treatment produces a dramatic benefit
  3. Stopping trials early
  4. Resources limited due to high cost
  5. Generalisability (RCTs are often carried out on specific types of patients for a relatively short period of time)
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33
Q

What is the relevance of bias and a confounder in RCTs?

A

Bias: Flaw in the methodology
Confounder: Another factor which is linked to both the exposure and the outcome

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34
Q

Advantages and disadvantages of expert (narrative) review?

A

Advantages:

  • Comprehensive survey
  • Answer a specific question

Disadvantages:
-Expert bias

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35
Q

What is a systematic review?

A

A systematic review attempts to identify, appraise and synthesize all the empirical evidence that meets pre-specified eligibility criteria to answer a given research question.
Considered “gold standard” due to avoidance/ minimisation of BIAS

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36
Q

Advantages and disadvantages of a systematic review

A

Advantages:

  • Comprehensive analysis of all the best primary evidence using explicit and reproducible methodology
  • Results can be combined and statistically analyses
  • Considered an evidence-based resource and the best guide to practice
  • Loss costly to review old studies than initiate a new one

Disadvantages:

  • Results often disagree
  • Publication bias
  • Very time consuming
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37
Q

What is meta analysis?

A

Combines qualitative and quantitative study data from several selected studies to develop a single conclusion which greater statistical power

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38
Q

Advantages and disadvantages of meta analysis?

A

Advantages:

  • Greater statistical power
  • Greater ability to extrapolate to the general population
  • Considered an evidence-based resource

Disadvantages:

  • Results often disagree
  • Heterogeneity of study populations
  • Very time consuming
  • Requires advanced statistical techniques
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39
Q

Define allergy

A

Disease following a response by the immune system to an otherwise innocuous antigen

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40
Q

What type of hypersensitivity does an allergy fall into?

A

Type I

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41
Q

Type I hypersensitivity:

  • Immune reactant?
  • Antigen?
  • Effector mechanism?
  • Example?
A

Immune reactant: IgE
Antigen: Soluble
Effector mechanism: Mast cell activation
Example: Asthma, Allergy

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42
Q

Type II hypersensitivity:

  • Immune reactant?
  • Antigen?
  • Effector mechanism?
  • Example?
A

Immune reactant: IgG
Antigen: Cell/matrix associated, cell surface receptor
Effector mechanism: Complement, FcR cells, Ab alters signalling
Example: Drugs, Chronic urticaria

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43
Q

Type III hypersensitivity:

  • Immune reactant?
  • Antigen?
  • Effector mechanism?
  • Example?
A

Immune reactant: IgG
Antigen: Soluble
Effector mechanism: Complement, phagocytes
Example: Arthus reaction

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44
Q

Type IV hypersensitivity:

  • Immune reactant?
  • Antigen?
  • Effector mechanism?
  • Example?
A

Immune reactant: Th1, Th2, CTL
Antigen: Soluble, cell-antigen
Effector mechanism: Macrophage activation, eosinophil activation, cytotoxicity
Example: Contact, Chronic asthma

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45
Q

Allergy is Ig_ mediated, and always occurs on
_______ exposure to an allergen, so an initial
_______ event has always taken place.

A

Allergy is IgE mediated, and always occurs on
SECONDARY exposure to an allergen, so an initial
EXPOSURE event has always taken place.

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46
Q

List the following immunoglobulins in order of highest serum level to lowest?

A

IgG > IgM > IgA > IgD > IgE

ie serum IgE levels are normally very low

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47
Q

Allergy occurs when IgE triggers what?

A

Allergy occurs when IgE triggers MAST CELL DEGRANULATION

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48
Q

5 mechanisms of IgE production

A
  1. IgE produced by plasma B cells in lymph nodes (or locally at the site of inflammation)
  2. IgE located mostly in tissue (hence low serum
    concentration), bound to Mast Cell surface through high affinity IgE receptor
  3. Certain antigens and routes of delivery appear to
    favour IgE production. Transmucosal at low doses
    is often a common route.
  4. CD4+ T cells of the Th2 phenotype that produce
    IL4 cytokines favour IgE responses
  5. Th2 T cells force B cells to switch the isotype of the Ig they secrete from IgM to IgE
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49
Q

What different molecules are produced by the following effector t cells:

  • CD8 cytotoxic
  • CD4 Th1
  • CD4 Th2
A

CD8 Cytotoxic:

  • Produces IFN-gamma, TNF-alpha
  • ->Targets cell lysis

CD4 Th1

  • Produces IFN-gamma, TNF-alpha, GM-CSF
  • ->Macrophage activation

CD4 Th2

  • Produced IL4, IL5 (cytokines)
  • ->B cell activation
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50
Q

What does GM-CSF mean?

A

Granulocyte macrophage colony-stimulating factor.

As cytokine (Cytokines are a category of signaling molecules that mediate and regulate immunity, inflammation and hematopoiesis.)

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51
Q

Common allergens (inhaled/injected/ingested/contacted)?

A

Inhaled: Plant pollens, Mold spores, Faeces of very small animals
Injected: Insect venoms, vaccines, drugs, therapeutic proteins

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52
Q

If an allergen induces degranulation further down the airway this results in ____

A

Allergic asthma

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53
Q

Allergic asthma features?

A

Bronchial constriction
Increased secretion of fluid and mucus = trapping inhaled air
-Chronic inflammation may ensue with continued presence of Th2 T cells, eosinophils, neutrophils
-Chronic asthma resulting in hyperreactive airways due to other irritants (e.g. cigarette smoke)

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54
Q

Clinical features of skin allergy

A

Allergens entering at skin sites cause RASHES
Wheal and flare due to vasodilation after Mast cell degranulation
Diffuse oedema present 8hrs later due to influx of lymphocytes attracted by chemokines

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55
Q

Ingested allergens reaction symptoms?
If allergen enters bloodstream?
Severe cases features?

A

2 main symptoms:

  • Activation of GI mast cells results in transepithelial fluid loss and smooth muscle contraction
  • -> DIARRHOEA and VOMITING

If allergen enters bloodstream –> generalised disseminated rash, urticaria, hives
In severe cases of food allergy, life threatening generalised anaphylaxis and CV collapse may occur

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56
Q

What are the chemical mediators of allergic responses?

A 
Mast cells granules (contain wide range of inflammatory mediators)
Lipids 
Toxic mediators
Cytokines
Enzymes
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57
Q

Role of lipids in allergic responses?

A 
Prostaglandins
-Increase vascular permeability 
-Increase body temp
Platelet activating factor
-Increase adhesion between endothelium and neutrophils 
Leukotrienes 
-Attract and activate neutrophils
-Increase vasc permeability
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58
Q

Role of toxic mediators in allergic response?

A 
Histamine
-Increases vascular permeability 
-Promotes fluid movement from vasculature by vasoconstriction
Heparin
-Inhibits coagulation
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59
Q

Role of cytokines in allergic response?

A

IL4, IL13 = Amplify Th2 response
Il3, Il5, GM-CSF = Promotes eosinophil activation and production
TNF-alpha = Pro-inflammatory, activates endothelium
Chemokine MIP-1alpha = Attracts macrophages and neutrophils

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60
Q

Treatment to prevent allergy

A

Two main types: Desensitisation and blockage of effector pathways
Aim: Shift response from IgE dominated to IgG dominated
Method: Patient injected with escalating doses of allergen leading to gradual shift from Th2 to Th1 T cells
Blocking agents: Anti-histamines in H1 receptor blocking.

Extra: Topical or systemic corticosteroids to supress chronic inflammation in asthma and rhinitis

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61
Q

Treatment of severe anaphylaxis

A

Treatment: Epinephrine (adrenaline) injection via Epi/Ana-pen
Results in smooth muscle contraction of BV = broncho dilation
0.15mg dose for children, 0.3mg dose for adult. Delivered in thigh. Second dose if no signs of improvement within 10-15mins

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62
Q

Why are economically developed societies more prone to allergies?

A

Early childhood exposure to Th1 inducing pathogen may prevents bias towards Th2 responses later.
This process is blocked in more hygienic environments hence more allergies present.

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63
Q

What is resistance?

Intrinsic vs acquired resistance?

A

When a previously susceptible organism is no longer inhibited by an antibiotic at levels clinically safe achievable concentrations
Acquired resistance= Occurs when a previously susceptible strain/species develops an increase in MIC that takes it beyond the therapeutic range.
Intrinsic resistance =When all strains of a species are resistant

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64
Q

What is intermediate resistance?

A

Resistance that can be treated with an increase from the standard dose

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65
Q

What is therapeutic index?

A

The difference between treatment dose and dose necessary to cause harm

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66
Q

What is MIC?

A

Minimum inhibitory concentration: The lowest concentration for an antibiotic that completely inhibits the growth of a bacterium

67
Q

What is MBC?

A

Minimum bactericidal concentration

The lowest dose that completely kills a bacterium

68
Q

What factors influence the breakpoint of antibiotic resistance?

A
  1. Distribution of MICs of target bacteria
  2. Achievable therapeutic conc in tissue
  3. Maximum achievable concentration
69
Q

Name 4 example of intrinsic resistance

A

Steptococci= Naturally resistant to aminoglycosides
Pseudomonas spp = Normally resistant to beta lactams
Mycoplasma spp= All resistant to beta-lactam antibiotics (as they lack of cell wall)
Enterobacteriaciae= All resistant to metronidazole

70
Q

Name 6 different mechanisms of resistance? Name either the agent acting or the component effected

A
  1. Enzymatic inactivation by destruction e.g. B-lactamases enzymes
  2. Enzymatic addition e.g. effects aminoglycosides
  3. Impermeability e.g. B-lactams
  4. Efflux on antibiotic out of cell e.g Effects tetracyclines, quinolones, macrolides
  5. Alternative pathways of virus to avoid antibiotic e.g. MRSA via mecA product pathway against flucloxacillin
  6. Alteration of binding site e.g. rifampicin, fluroquinolones, sulphonamides
71
Q

How do fluroquinolones function as antibiotics?

How is resistance developed?

A

The fluoroquinolones are the only direct inhibitors of DNA synthesis; by binding to the enzyme-DNA complex, they stabilize DNA strand breaks created by DNA gyrase and topoisomerase IV.
Tertiary complexes of drug, enzyme, and DNA block progress of the replication fork

Quinolone resistance due to reduced binding to DNA by DNA gyrase

72
Q

What genes at involved in quinolone resistance? What is consequence of gene mutation?

A

Genes: gryA and parC
Point mutations in the genes change the affinity of the proteins for DNA
Mutation in one gene= Low level resistance
Mutation in both genes= high level resistance

73
Q

What are 3 modes of resistance transmission?

A
  1. Transformation e.g. penicillin in S. pneumonia
  2. Conjugation e.g. B-lactamases bacterteria
  3. Transposons e.g. erythromycin in S. pyogenes
74
Q

What is the mechanism of conjugation in antibiotic resistance transmission?

A

The plasmids in bacteria encode resistance determinants. These can be transmitted between cells, allowing characteristics to be shared rapidly

75
Q

What are transposons and integrons?

A

Small segments of DNA that encode their own transmission. Allows genome plasticity and may collect resistance determinants

76
Q

What is a superbug?

Name 4 examples

A

Organism that has gained resistance to a critical antibiotic or multiple antibiotics. Commonly transmitted in hospital
E.g.
-MRSA: Meticillin Resistant Staph Aureus
-GISA: Glycopeptide Resistance Staph Aureus
-VRE: Vancomycin Resistance Enterococcus
-ESBLs: Expanded spectrum beta-lactamases

77
Q

What are carbapenemases?

Name 3 different groups?

A

Carbapenemases are β-lactamases with versatile hydrolytic capacities. Bacteria producing these β-lactamases may cause serious infections in which the carbapenemase activity renders many β-lactams ineffective.

Groups:

  • KPC (Klebsiella pneumonia carbapenemase)
  • NDM (New Delhi metallo-betalactamase)
  • Oxa-48 group
78
Q

How do we address antibiotic resistance?

A
  1. Optimise the treatment of bacterial disease
  2. Better diagnosis
  3. Focussed treatment
  4. Appropriate length of course
79
Q

How to treat resistant bugs?

A

Do culture
Susceptibility testing
Use the most bactericidal drug available
Consider the use of combinations

80
Q

Examples of yeasts and their disease entity

A

Candida spp. = Thrush, fungaemia
Cryptococcus neoformans = Meningitis, pneumonia and fungaemia
Pityriasis versicolor= Chronic skin infection
System yeasts e.g. histoplasma capsulatum = Pulmonary or disseminated infections

81
Q

Examples of yeasts and their disease entity

A

Candida spp. = Thrush, fungaemia
Cryptococcus neoformans = Meningitis, pneumonia and fungaemia
Pityriasis versicolor= Chronic skin infection
System yeasts e.g. histoplasma capsulatum = Pulmonary or disseminated infections

82
Q

Examples of filamentous fungi and their disease entity?

A

Aspergillus spp., Mucor, Rhizopius, Absidia = Pulmonary ocular infection, “farmer’s lung” bronchopulmonary aspergillosis, fungaemia

Dermatocytes = Chronic infection of the skin, nails, kerion

83
Q

What are the main groups of anti fungal drugs?

A

Tri-azole drugs
Polyenes
Echinocandins
Misc: Flucytosine, Terbinafine, griseofulvin

84
Q

Name 4 tri-azole drugs?

Mode of action?

A
  1. Fluconazole. Oral admin. Penetrates CSF = treats fungal meningitis. Excreted in urine largely unchanged = treats candiduria
  2. Itraconazole. Require acidic environement of stomach for optimal absorption. Associated with liver damage
  3. Posaconazole. Treats invasive fungal infection unresponsive to conventional treatment
  4. Voriconazole. Broad spectrum, used in life-threatening infections

Mode of action: Block p450 and sterol 14 alpha demethylase in the cell wall.

85
Q

When is flucytosine used?

Mode of action?

A

Treat systemic and fungal infections.
Adjunct to amphotericin in cryptococcal or severe systemic candidiasis
Mode of action: Inhibits protein synthesis

86
Q

Name two polyenes
Administration? Uses?
Mode of action

A

Amphotericin: IV for systemic fungal infections. Highly plasma protein bound. Lipid formulations are less toxic
Nystatin: For oral, oropharyngeal and perioral infection by local application
Mode of action: Binding to ergosterol leading to pore formation in CM which allows leakage of intracellular cations.

87
Q

Echinocandin anti-fungals

  • 3 examples
  • Mechanism
  • Uses?
  • Limitation
A

Examples: Anigulafungin, caspfungin, micofungin
Mechanism: Inhibits beta-(1,3)-D-glucan synthase
Use: Aspergillus spp and candida spp. ONLY
Limitations: Not effective against fungal infections of the CNS

88
Q

Terbinafine:
-Mode of action?
Uses?

A

Mode of action: Inhibits squalene oxidase leading to build up of squalene (toxic) and ergosterol in cell wall. Results in fungal cell death
Uses: Dermatophyte infections of the nails, ringworm infections where oral therapy appropriate

89
Q

Griseofulvin
Uses?
Mode of action?

A

Use: Dermatpphyte infections of the skin, scalp, hair and nails
Mode of action: Ihibits fungal mitosis

90
Q

Treatment of invasive candidiasis?

A

1st choice: Echinocandin
2nd choice: Fluconazole
3rd choice= Amphotericin. 1st choice for CNS candidiasis

91
Q

Treatment of superficial candidiasis

A

Treated locally with miconazole
Widespread infection requires systemic antifungal treatment (fluconazole)
Vaginal candidiasis= 1. Fluconazole 2. Intraconazole

92
Q

Location of aspergillosis?

Treatment of aspergillosis `

A

Location: Resp tract but in severely immunocompromised patients can affect the heart, brain and skin

Treatment

  1. Voriconazole
  2. Lipsomal amphotericin
93
Q

Treatment cryptococcal meningitis

A
  1. Amphotericin via IV and flucytosine by IV for 2 weeks. Followed by fluconazole orally for 8 weeks
94
Q

Treatment for systemic fungal infection (e.g. histoplasmosis)?

A

Parenteral iterconazole for immunocompromised patients
Patenteral amphotericin in patients with fulminant/severe infections

Following treatment, itraconazole for prophylaxis against relapse

95
Q

What is the cause of a type II hypersensitivity reaction?

A

Result of antibodies, usually IgG, binding to components of cell membranes or extracellular matrix. Can be self components or exogenous components

96
Q

What is Goodpasture’s syndrome?

A

When antibodies bind to basement membrane collage type IV

Causes: Glomerulonephritis in kidney and pulmonary haemorrhage in lung

97
Q 
Type III hypersensitivity:
Cause?
Target?
Clearance?
Risk of deposition?
A

Caused by antibody, usually IgG, but also IgM
Type III antibodies directed to soluble antigens
Cleared by reticuloendothelial system(RES): Macrophages, neutrophils in the liver, spleen and bone marrow that ingest and degrade immune complexes
Excess immune complex deposition in tissues leads to pathology

98
Q

Describe the progression of a type III hypersensitivity response as the ratio of antigen to antibody changes

A
  1. Antigen > antibody. Small immune complexes form that do not fix complement and are not cleared from circulation
    2 Antigen = antibody. Immune complexes are formed that can fix complement and are cleared from the circulation.
  2. Antibody > antigen. Immune complexes of an intermediate size are formed that can fix complement and are cleared from the circulation
99
Q

Describe the events of type III hypersensitivity in immune individual

A
  1. Locally injected antigen in immune individual with IgG antibody
  2. Local immune-complex formation
  3. Activation of complement releases inflammatory mediators and induces mast cell degranulation
  4. Local inflammation, movement of fluid + protein into tissue, blood vessel occlusion
100
Q

Name 5 sites of type III immune complex deposition

A 
Glomeruli in kidneys: Due to filtration
Blood vessel wall: Causes vasculitis 
Synovial membrane: In rheumatoid arthritis 
Skin: Causes rashes
Systemic sites
101
Q

Type IV hypersensitivity

-Mechanism?

A

Mechanism:

  • Entirely cell-mediated
  • Complement does not play a role
  • Reacts caused by CD4+ delayed type hypersensitivity (DTH) reactions.
  • Macrophages that cause damage are not specific (harms infected and non-infected tissue)
102
Q

Stages of type IV hypersensitivity

A
  1. Antigen is introduced into subcutaneous tissue and processed by local antigen-presenting cells
  2. A TH1 effector cell recognises antigen and releases cytokine which act on vascular endothelium
  3. Recruitment of T cells, phagocytes, fluid and protein to site of antigen
103
Q

What are contact sensitivities?

A

A special category of DTH reaction in which antigen is not an infectious agent but a chemical that binds to cell surface
E.g. Heavy metal, poison ivy

104
Q

Autoimmune diseases can be classified in the same way as hypersensitivity reactions.
Name 3 autoimmune diseases for Type II, III and IV hypersensitivities?

A

Type II: Autoimmune hemolytic anaemia, Acute rheumatic fever, Goodpasture’s syndrome
Type III: Mixed essential cryoglobulinemia, SLE, rheumatoid arthritis
Type IV: IDDM, rheumatoid arthritis, MS

105
Q

What are the 3 main approaches to treating established cancers?

A
  1. Surgical excision
  2. Radiotherapy
  3. Chemotherapy
106
Q

What are the 4 types of traditional agent in chemotherapy?

A

Alkylating agents
Antimetabolites
Cytotoxic antibiotics
Plant derivatives

107
Q

What is the mechanism for alkylating agents?

Name 6 major groups

A

Mechanism: Intrastrand linking and crosslinking of DNA. Normally guanine residues exist in the keto tautomer, allowing H bonding with cytosine. When alkylated, the enol tautomer is formed, leading to mispairing with thymine residues
Triggers cell death by apoptosis

Groups:

  1. Nitrogen mustards e.g. cyclophosphamide
  2. Ethylenimines e.g. thiotepa
  3. Alkylsulphonates e.g. Busulphan
  4. Hydrazines and triazines e.g. Temozolomide
  5. Nitrosoureas e.g. Lomustine, carmustine
  6. Platinum based compounds e.g. Cisplatin
108
Q

What are the 3 main groups of antibmetabolites?

A
  1. Antifolates e.g. Methotrexate
  2. Antipyrimidines e.g. 5-FU, gemcitabine
  3. Antipurines e.g. Mercaptopurine, thioguanine
109
Q

Name 4 examples of cytotoxic antibiotics?

A

Antracyclines e.g. doxorubicin
Dactinomycin
Bleomycin
Mitomycin

110
Q

Which of the alkylating agents:

  1. Are lipid soluble, therefore can cross BBB and are used against tumours of the brain and meninges?
  2. Have a selective effect on the bone marrow. At low dosage, depresses formation of granulocytes and platelets. At high dosage, depresses formation of RBC. Used in chronic granulocytic leukemia
A
  1. Nitrosoureas: Lomustine and Carmustine

2. Alkylsuphonates: Busulphan

111
Q

What is the structure of cisplatin? How does it alter then it enters the cell?

A
  • Water soluble
  • Planar coordination complex
  • Contains central platinum atom surrounded by two chlorine atoms and two ammonia groups

On entering the cell, Cl- dissociates leaving a reactive complex that reacts with water and then interacts with DNA

112
Q

Plant derivatives:

  • Mechanism
  • Groups
A

Mechanism: Spindle poisons (affects microtubule function and prevent mitotic spindle formation)

Groups:

  • Vinca alkaloid e.g. Vincristine, vinblastine
  • Taxanes e.g. Paclitaxcel, docetaxel
  • Camptothecines e.g. Irinotecan
  • Etoposide
113
Q

What are the 5 main drawbacks of current cancer chemotherapy?

A
  1. Targets cell proliferations, not the more lethal properties of invasiveness and metastasis
  2. Non-specific cell killers, vs being aimed at the particular changes that make a cell malignant
  3. The development of resistance
  4. Tumour stem cells remain. Due to therapeutic doses not sufficient for total elimination
  5. Patient compliance due to the side effects
114
Q

What are Novel targeted agents?

Give 3 examples of their use as anticancer drugs?

A

Monoclonal antibodies and small molecules

RITUXIMAB targets a B cell surface protein and is used for B cell lymphomas
TRASTUZUMAB targets epidermal growth factor receptor and is used for breast cancer
IMATINIB inhibits BCR-ABL genes signalling pathays and is used for chronic myeloid leukaemia

115
Q

What is the relevance of personalised medicine in SNCLC?

A

EGFR mutation analysis = Activating mutations. Treat with erlotibin
KRAS mutation analysis = activating mutations. No drug treatment
ALK rearrangement analysis = Fusion. Treat with Crizotinib

116
Q

Role of personalised medicine in colorectal cancer?

A

CETUXIMAB in anti-EGFR monoclonal antibody therapy
If KRAS/NRAS mutation analysis shows no mutations = CETUZMAB plus chemotherapy. RAS mutation predicts a poor response to therapy.

Screening for hereditary non-polyposis colorectal cancer

117
Q

Role of personalised medicine in melanoma management?

A

Melanoma= Due to mutations which activate the photo-oncogenes called BRAF. Leading to tumour growth.

VERMURAFENIB acts as mutation B-Raf inhibitor
NRAS mutations = MEK inhibitors/combinations
IMATINIB: for KIT mutations

118
Q

Role of personalised medicine in brains tumours?

A

TEMOZOLOMIDE: Alkylating agents (radiation therapy used as first line)
Methylyation of MGMT promoter gene. This is a gene repair enzyme which counteracts the damage caused by alkylating agent.

119
Q

How are soft tissue and bone tumours diagnosed?

A

Current: FISH analysis or Ewing’s sarcomas, alveolar rhabdomyosarcomas, leiomyosarcomas, fibromyxoid sarcomas

Molecular studies now used to complement morphological diagnosis

120
Q

The PD-1 is expressed on the surface of activated _ _____

Its ligands, PD-L1 and PD-L2 are commonly expressed on the surface of ________ ______ or ___________.

A

The PD-1 is expressed on the surface of activated T cells.

Its ligands, PD-L1 and PD-L2 are commonly expressed on the surface of dendritic cells or macrophages.

121
Q

What is the role of nivolumab in the personalised medical treatment of melanoma and sq NSCLC?

A

Targets PDL-1 mediated signalling and restores anti-tumour immunity
Anti-PD-L1
Binds to cancer cells to enhance the immune response.

122
Q

What is the role of Ipilimumab in the personalised medical treatment of metastatic melanoma?

A

Anti-CTLA-4 antibody
Recruits immune system to attack cancer cells.

CTLA- Cytotoxic T Lymphocyte-associated Antigen. Regulates t cell activation. Antibodies which block interaction between CTLA and its ligands increase immune response

123
Q

Describe the innate lung defence mechanisms

A

Nasal mucus
Ciliated cells
Mucociliary clearance elevator (flicked upwards to be swallowed to spat out)
Defensins: Small, cationic proteins, sticks to pathogen, non-specific, as its comformaton changes it punctures the membrane
Alveolar macrophages: Picks up bacteria and fungi
Polymorphonuclear leucocytes
Complement and circulating factors

124
Q

What 5 ways can be mucociliary clearance elevator be compromised?

A
  1. Genetic diseases e.g. Cystic fibrosis, Kartagener’s syndrome
  2. Occupational diseases e.g. Silicosis, pneumoniosis
  3. Smoking: Disrupts cilia function
  4. Previous infection e.g. previous pneumonia
  5. Obstruction of the bronchi e.g. Foreign body inhalation
125
Q

What do respiratory bacteria have to do to cause pneumonia?

A

Colonise the nasopharynx or be inhaled into the alveolus
Adhere to respiratory cells
Evade the immune system
Multiply
Express virulence factors that cause disease

126
Q

What is the acute response to the respiratory tract to bacteria?

A

Complement

  • Bacterial cell wall components activate the alternative complement pathway
  • Complement components attract PMNs and macrophages
  • Complement components attached to bacteria opsonise them

Neutrophils: Respiratory burst is the rapid combination of -OH and Cl to produce bleach which kills bacteria

127
Q

What are the 3 features of acute inflammation and where in the resp tract are these features most relevant?

A

Vasodilation: Nasal passages
Exudation: Alveoli
Oedema: Epiglottis

128
Q

What are the 5 different mechanisms that bacteria in the respiratory tract are overcome?

A 
Phagocyte action (PMNs and macrophages)
Engulfed
Lytic enzymes kill bacteria e.g. myeloperoxidase 
Reactive oxygen intermediates 
Halide mechanisms
129
Q

What is the mechanism and importance of neutrophil clearance in the respiratory tract?

A

Involved in respiratory burst and killing via lytic enzymes
Mechanism: Apoptosis and clearance by phagocytosis by macrophages
Importance: If clearance doesn’t occur, build up of neutrophils = pus. Pus in airways = pneumonia

130
Q

List 4 features of chronic inflammation in the airways and where in particular they impact

A

Granulation tissue: Alveoli
Macrophages
Fibrosis
Repair/remodelling: Trachea, main bronchi, bronchioles

131
Q

What is bronchiolitis?

A 
Concentric fibrosis (due to infection) of the submucosa of small bronchioles results in obliteration of the lumen. 
Primary bronchiolitis: Respiratory infection caused by viruses, especially RVS in infants 
RSV= Respiratory syncytial virus
132
Q

What is pneumonia?

Two types?

A

Acute inflammation: Inflammation, vasodilatio, exudation, inflammatory cells come

Two main types:

  1. Lobar: Alveoli filled with macrophage and neutrophils. Neutrophils turn into pus. Caused by streptococcus pneumoniae
  2. Bronchopneumonia: Patchy consolidation, multiple lobes affected but not whole lobes. Secondary to obstruction.
133
Q

What are cases that have remodelling/bronchiectasis present?

A 
TB
Cystic fibrosis
Obstruction
Post-viral
Chronic suppuration
134
Q

4 ways that the immune defence of the resp tract can be compromised?

A

Congential
Acquired e.g. HIV, leukemia
Opportunistic infection
Organisms e.g. TB, streptococcus pneumoniae

135
Q

Risk factors for tb

A

The immunocompromised

Socioeconomic: Young, overcrowding, malnourishment, alcoholism, civil disruptions

136
Q

What is the difference between primary, secondary and military TB spread?

A

Primary: Produces small mid-zone lesion with involvement of hilar lymph nodes. Caseous necrosis present. Mechanism of type 4 hypersensitivity
Secondary tb: Lesions are apical and bilateral
Miliary tb: The lungs and other organs contain small granulomas

137
Q

What is a pneumothorax?

A

Air in the pleural cavity which causes it to deflate or collapse entirely

138
Q

Demonstrate knowledge of the development of treatment for tuberculosis

A

Discovery of the concept of antibiotics by Waksman and Schatz (based on theory that soil produces agents to kill mycobacterium)
Streptomycin discovered, developed patient resistance

139
Q

Describe the currently recommended/approved regimen for tuberculosis for:

  1. Initial phase
  2. Continuation phase
A 
INITIAL PHASE
Drugs: (RIPE)
-Isoniazid
-Rifampicin
-Pyrazinamide
-Ethambutol 
Length: 8 weeks
CONTINUATION PHASE
Drugs:
-Isoniazid 
-Rifampicin 
Length: 18 weeks
140
Q

Isoniazid:

  • Action?
  • Problems with toxicity?
  • Resistance?
A

Action: Inhibits mycolic acid biosynthesis in the TB cell wall
Toxicity relatively low: Can cause hepatitis, peripheral neuropathy (give pyridoxine) and rheumatologic rash/nausea
Resistance: Overall 10%, varies by population

141
Q

Rifampicin
Action?
Toxicity?
Drug interactions?

A

Action: Inhibits bacterial DNA-dependent RNA polymerase of tb cells
Toxicity:
-Hepatitis
-Discolouration of urine, tears and sweat
Drug interactions: CYP 450 induction. Increases clearance of other drugs (decreasing activity) e.g. warfarin, antiretrovirals

142
Q

What is the main side effect of toxicity derived from ethambutal?

A

Optic neuritis

Loss of colour vision

143
Q

What are the second line drugs used for treatment fo tb when multi-resistance occurs?

A 
Fluroquinolones
Aminoglycosides (streptomycin, kanamycin)
Cylcoserine
PAS
Ethioamide
Clofazamine
144
Q

What is DOTS?
5 components?
Reason for failure?

A

Directly Observed Short Course Treatment
5 components:
1. Political financing
2. Case detection via bacteriology
3. Standardised treatment with supervision and patient support
4. Effective drug supply/management system
5. Monitoring and evaluation system. Impact measurements

Failed as taking 6 months of drugs wasn’t sustainable

145
Q

4 general principles of treating tb

A
  1. Requires more than one drug to which the organisms are susceptible (due to resistance)
  2. Appropriate drug doses
  3. Regular dosing
  4. Sufficient total period of time on therapy
146
Q

Why does a mutation occur?

What determines survival of the mutant?

A

Due to failure of fidelity in polymerases and proof reading functions

Survival depends on:

  • Degree of resistance encoded
  • Effect on the function of the mutated gene
147
Q

What happens to the risk of resistance as the number of drugs in increased?

A

It decreases

e.g.
Resistance to rifampicin arises 10-9/cell division
Resistance to isoniazid is 10-7/cell divison
Making the combined risk 10-16/cell division.

148
Q

What 4 conditions increase the risk of resistance occurring?

A
  1. Higher bacterial load
  2. Taking therapy irregularly i.e monotherapy
  3. Patients taking inactive drugs (counterfeit)
  4. If physician provide the wrong prescription
149
Q

Conditions associated with MDRTB (multi drug resistance tb)?

A

Cavitatory disease: Big cavities, high bacterial load
Empyema: Big load of bugs, hard to get drugs in
HIV: Less able to control bacterial load
Previous, possibly inadequate treatment for tb

150
Q

How is MDRTB controlled?

A
  1. Identify patients at risk
  2. 24hr Z-N service
  3. PCR detection of rpoB mutations (rifampicin resistant)
  4. Isolate at risk patients
  5. Treat effectively
  6. Prevent emergence of new cases
151
Q

How are MDRTB patients isolated?

A

Side room
Negative pressure ventilation (6 air changes per hour)
Effective masks for staff
Careful consideration of discharge

152
Q

What is MDRTB such a worry?

A

Patients who have MDRTB remain infectious for longer.
Susceptibility is rarely performed, so we don’t know what we’re treating
Patients are exposed to successive inadequate regimens, so resistance grows.

153
Q

How is the emergence of new cases of MDRTB prevented?

A

Better, shorter treatment regimens
Open access to diagnostic services
Specialist management of cases
Contact tracing: Done by nurses to contact people who made contact
Molecular epidemiology
Integrated tb diagnostic and clinical service

154
Q

Factors associated with a poor outcome for TB patients

A 
Male gender
Smear positivity i.e. higher bacterial load 
Alcohol
Low BMI
Fluoroquinolone resistance
Presence of an XDRTB patient
155
Q

What is XDRTB

A

Extrensively drug-resistant TB
Resistant to isoniazid and rifampin, plus nay fluoroquinolone and 1/3 injectable second-line drugs
Only available drugs are toxic and not very active

156
Q

Bedaquiline:
Administration?
Action?
Current extend of usage?

A

Orally active

Inhibits ATPase in mycobacterial cell wall that pumps protons out of the cell

Approved for treatment of MDRTB in combination with other agents

157
Q

Name 3 drugs in clinical development for treatment of MDRTB and VDRTB?

A

Pretomanid- an imidazole
Delamind- an imidazole now registered for the treatment of MDRTB
STRAND trial: Pyrazinamide/PA824/ Moxifloxacin

158
Q

What determines the breakpoint in breath holding?

A

Reason for forced breathing is due to pH changes detected by central receptors in medulla (which are sensitive to CO2 changes).

Held breath –> Respiratory acidosis

159
Q

Why can you hold your breath for lung following hyperventilation?

A

During hyperventilation you blow of CO2, this causes respiratory alkalosis

You can hold your breath for longer as there needs to be a greater change in pH for alkalosis -> acidosis

160
Q

How do you calculate FEV-1%?

A

FEV1/FVC x 100
(Normal value = 80%)
Used to diagnose obstructive and restrictive respiratory disorders
It represents the percentage of a person’s vital capacity that they are able to expire in the first second of forced expiration.

161
Q

Effect of restrictive lung order on vitalograph?

A

Both forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) are reduced
Decline in FVC is more than that of FEV1, resulting in a higher than 80% FEV1/FVC ratio

162
Q

What is restrictive lung disease? Examples

A

In a restrictive lung disease, the compliance of the lung is reduced, which increases the stiffness of the lung and limits expansion. In these cases, a greater pressure (P) than normal is required to give the same increase in volume (V). Common causes of decreased lung compliance are pulmonary fibrosis, pneumonia and pulmonary edema.

163
Q

What is obstructive lung disease? Examples

A

In an obstructive lung disease, airway obstruction causes an increase in resistance. During normal breathing, the pressure volume relationship is no different from in a normal lung. However, when breathing rapidly, greater pressure is needed to overcome the resistance to flow, and the volume of each breath gets smaller. Common obstructive diseases include asthma, bronchitis, and emphysema.

MD3001 (12 decks)

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