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Medicine Sem 2 > Case 2 > Flashcards

Case 2 Flashcards

1
Q

what is tidal volume?

A

the volume of air displaced between normal inspiration and expiration (0.5L)

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2
Q

what is inspiratory reserve volume?

A

the extra volume of air that can be inspired over and above the normal tidal volume when the person inspires with full force (3L)

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3
Q

what is expiratory reserve volume?

A

the maximum extra volume of air that can be expired by forceful expiration after the end of a normal tidal expiration (1.1L)

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4
Q

what is residual volume?

A

the volume of air remaining in the lungs after the most forceful expiration (1.2L)

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5
Q

what is inspiratory capacity?

A

tidal volume + inspiratory reserve volume

the amount of air a person can breathe in, beginning at the normal expiratory level and distending the lungs to the maximum amount

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6
Q

what’s functional residual capacity?

A

expiratory reserve volume + residual volume

the amount of air that remains in the lungs at the end of normal expiration

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7
Q

what’s vital capacity?

A

inspiratory reserve volume + tidal volume + expiratory reserve volume

the maximum amount of air a person can expel from the lungs after first filling the lungs to their maximum extent and then expiring to the maximum extent

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8
Q

what’s total lung capacity?

A

inspiratory reserve volume + tidal volume + expiratory reserve volume + residual volume

the maximum volume to which the lungs can be expanded with the greatest possible effort

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9
Q

what’s the difference between pulmonary volumes and capacities in men and women?

A

20-25% less in women than in men

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10
Q

arterial oxygen tension

  • normal range
  • hypoxaemia
  • hypoxia
A
  • normal range: 12.0-13.3 kPa
  • decreased PaO2 is known as hypoxaemia

Note:

  • hypoxia = the failure of oxygenation at the tissue level
  • hypoxaemia = where the PaO2 is below the normal range
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11
Q

what’s arterial carbon dioxide tension?

  • normal range
  • what does it lead to
A
  • normal range: 4.8-6.1 kPa
  • increased in PaCO2 (hypercapnia) usually results in a decreased pH of the blood due to its conversion into carbonic acid which then dissociates into H+ ions and HCO3- (bicarbonate ions)
  • this will cause increased respiratory rate to get more blood to the lungs for gas exchange (of CO2 out of the body)
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12
Q

what is the normal pH of your arterial blood?

A

7.35-7.45

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13
Q

what does pulse oximetry do?

A

it measures the difference in absorbance of light by oxygenated and deoxygenated blood to calculate its oxygen saturation (SaO2)

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14
Q

normal values for peak expiratory flow rate (PEFR)?

A

normal values are dependent on height:

  1. 5m = 350 L/min
  2. 6m = 400 L/min
  3. 7m = 450 L/min
  4. 8m = 500 L/min
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15
Q

what does spirometry measure? what is normal?

A

• The spirometer measures the forced expiratory vital capacity (FVC) and the forced expiratory volume at the end of the first second (FEV1).
• FEV1 is expressed as a percentage of the FVC, i.e. how much of the FVC is exhaled by the end of the first second.
• The image compares the FVC of a normal person to a person with airway obstruction.
• Healthy person:
- Larger lung volume.
- Larger FEV1 (80%).
• Airway obstruction:
- Lower lung volume.
- Lower FEV1 (47%).
• In serious airway obstruction, as often occurs in acute asthma, the FEV1 can decrease to less than 20%.

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16
Q

what is type I and type II respiratory failure?

A

type I: hypoxia without hypercapnia

type II: hypoxia with hypercapnia

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17
Q

what’s the equation for partial pressure?

A

partial pressure = concentration of dissolved gas/solubility coefficient

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18
Q

describe the solubility coefficient

A

- Some types of molecules, especially carbon dioxide, are physically or chemically attracted to water molecules, and so are more soluble, whereas others are repelled, and so are less soluble.
- Attraction to water molecules means more dissolved gas molecules without a change in the partial pressure within the solution.
- Repulsion togase water molecules develops high partial pressure with fewer dissolved gas molecules.
- The higher the solubility coefficient, the lower the partial pressure.

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19
Q

describe the partial pressures of oxygen and carbon dioxide

A
  • At atmospheric pressure (=760 mmHg), carbon dioxide is 20 times as soluble as oxygen (it has a solubility coefficient which is 20 times greater than that of oxygen).
  • Therefore, the partial pressure of carbon dioxide is one-twentieth that exerted by oxygen.
  • As solubility coefficient increases, the partial pressure decreases.
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20
Q

why is the composition of alveolar air and atmospheric air different?

A
  1. Alveolar air is only partially replaced by atmospheric air with each breath.
  2. Oxygen is constantly being absorbed into the pulmonary blood from the alveolar air.
  3. Carbon dioxide is constantly diffusing from the pulmonary blood into the alveoli.
  4. Dry atmospheric air that enters the respiratory passages is humidified even before it reaches the alveoli.
     -As soon as the atmospheric air enters the respiratory passages it is exposed to the fluids that cover the respiratory surfaces.
  • alveolar air has more CO2 and less O2 than inhaled air
  • during exhalation, this alveolar air mixes with air in the dead spaces of the lungs producing exhaled air
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21
Q

why is slow replacement of alveolar air important?

A

- Important in preventing sudden changes in gas concentrations in the blood.
- This makes the respiratory control mechanism much more stable.
- It helps prevent excessive increases and decreases in…
o Tissue oxygenation
o Tissue carbon dioxide concentration
o Tissue pH
…when respiration is temporarily interrupted.

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22
Q

why when less air is expired, is there a greater concentration of oxygen in the expired air?

A

because most of the air expired will be dead space air

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23
Q

what are the different layers of the respiratory membrane?

A
  1. a layer of fluid lining the alveolus and containing surfactant
  2. the alveolar epithelium composed of thin epithelial cells (simple squamous cells)
  3. an epithelial basement membrane
  4. a thin interstitial space between the alveolar epithelium and the capillary membrane
  5. a capillary basement membrane that in many places fuses with the alveolar epithelial basement membrane
  6. the capillary endothelial membrane
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24
Q

what is diffusing capacity?

A

volume of a gas that will diffuse through the membrane each minute for a partial pressure difference of 1 mmHg

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25
Q

what is the diffusing capacity of oxygen and what can this be used to work out?

A
  • In the average young man, the diffusing capacity for oxygen, under resting conditions averages 21 ml/min/mmHg.
  • The mean oxygen pressure difference across the respiratory membrane during normal, quiet breathing is about 11 mmHg.
  • 21 ml/min/mmHg x 11 mmHg = 230 ml/min.
  • This means that, normally, 230 ml of oxygen diffuse through the respiratory membrane each minute; this is equal to the rate at which the body uses oxygen.
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26
Q

why is there a change in oxygen diffusing capacity during exercise?

A

• The diffusing capacity for oxygen increases up to 3 times.
• This increase is caused by several factors:
 - Opening up of many previously dormant pulmonary capillaries or extra dilation of already open capillaries, thereby increasing the surface area of the blood into which the oxygen can diffuse.
- A better match between the ventilation of the alveoli and the perfusion of the alveolar capillaries with blood, called the ventilation/perfusion ratio.

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27
Q

how can someone suffer severe respiratory distress despite having both normal total ventilation and normal total pulmonary blood flow?

A
  • Normally to some extent, and especially in many lung diseases, some areas of the lungs are well ventilated but have almost no blood flow, whereas other areas may have excellent blood flow but little or no ventilation.
  • This leads to impaired gas exchange.
  • The person may suffer severe respiratory distress despite both normal total ventilation and normal total pulmonary blood flow, but with the ventilation and blood flow going to different parts of the lungs.
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28
Q

describe V/Q ratio in quantitative terms

A
  • when the ventilation is zero, yet there is still perfusion of the alveolus, the V/Q is zero
  • when there is adequate ventilation but zero perfusion, the ratio is infinity
  • at a ratio of either zero or affinity, there is no gas exchange through the respiratory membrane of the affect alveoli
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29
Q

what happens when V/Q is equal to zero?

A
  • the air in the alveolus comes to equilibrium with the blood oxygen and carbon dioxide
  • venous blood perfuses the pulmonary vessels
  • the gases in this venous blood equilibrate with the alveolar gases
  • normal venous blood has a PO2 of 40 mmHg and a PCO2 of 45 mmHg
  • when V/Q = 0, these partial pressures of O2 and CO2 are the normal partial pressures of these gases in alveoli that have blood flow but no ventilation
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30
Q

what happens when V/Q = infinity?

A
  • alveolar air comes to equilibrium with the humidified inspired air
  • the inspired air loses no oxygen to the blood and gains no carbon dioxide form the blood
  • normal inspired and humidified air has a PO2 of 149 mmHg and a PCO2 of 0 mmHg
  • when V/Q = infinity, these parital pressures of O2 and CO2 are the normal partial pressures of these gases in alveoli that have ventilation but no blood flow
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31
Q

what happens when V/Q is normal?

A
  • When there is normal alveolar ventilation and normal alveolar perfusion, gas exchange through the respiratory membrane is optimal.
  • Alveolar PO2 is normally 104 mmHg, which lies between that of the inspired air (149 mm Hg) and that of venous blood (40 mm Hg).
  • Alveolar PCO2 is normally 40 mmHg, which lies between that in venous blood (45 mmHg) and that in inspired air (0 mmHg).
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32
Q

what is the physiologic shunt?

A
  • Whenever Va/Q is below normal, there is inadequate ventilation (reduced Va) to provide the oxygen needed to fully oxygenate the blood flowing through the alveolar capillaries.
  • A certain fraction of the venous blood passing through the pulmonary capillaries does not become oxygenated.
  • This fraction is called shunted blood.
  • The total quantitative amount of shunted blood per minute is called the physiologic shunt.
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33
Q

what is the physiologic dead space?

A
  • Whenever Va/Q is above normal, the alveolar perfusion is low (reduced Q), there is far more available oxygen in the alveoli than can be transported away from the alveoli by the flowing blood.
  • The ventilation of these alveoli is said to be wasted.
  • The ventilation of the anatomical dead space areas of the respiratory passageways is also wasted.
  • The sum of these two types of wasted ventilation is called the physiologic dead space.
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34
Q

describe and explain abnormal V/Q in the upper and lower normal lung

A

Upper Lung:
- Normally, in the upright position, both alveolar perfusion and alveolar ventilation are less in the upper part of the lung than in the lower part.
- Alveolar perfusion is decreased more than ventilation is.
 - Therefore, at the top of the lung, Va/Q is too high causing moderate degree of physiologic dead space in this area of the lung.

Lower Lung:
- In the bottom of the lung, there is slightly too little ventilation in relation to blood flow, with Va/Q being too low.
- In this area, a small fraction of the blood fails to become normally oxygenated, and this represents a physiologic shunt.

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35
Q

how long does it take for blood in the pulmonary capillaries to become oxygenated? how long does the blood normally stay in the capillaries for?

A
  • The PO2 rises almost to that of the alveolar air by the time the blood has moved a third of the distance trough the pulmonary capillary, becoming almost 104 mmHg.
  • The blood normally stays in the capillaries three times as long as needed to cause full oxygenation (saturation).
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36
Q

due to increased cardiac output, the time that blood remains in the pulmonary capillary may be reduced to less than half the normal amount during exercise - how does it still become sufficiently oxygenated ?

A

• Yet, due to the speed of saturation the blood still becomes almost saturated with oxygen.
• This is because:
1. Normally, the pulmonary blood is nearly fully saturated by the time the blood has moved a third of the distance trough the capillary. Therefore, during exercise, even with a shortened time of exposure in the capillaries the blood can still become nearly fully oxygenated.
2. The diffusing capacity increases almost threefold during exercise due to:
 - Increased surface area of capillaries participating in the diffusion (vasodilation).
- A more nearly ideal ventilation/perfusion ratio in the upper lung (reduced physiologic shunt).
• There is also increased ventilation at the start of exercise to reach aerobic conditions is as less time as possible.
• The ventilation is constantly regulated during exercise by peripheral chemoreceptors.
- The chemoreceptors sense increase in CO2 more than a decrease in O2.

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37
Q

what happens at the start of exercise in terms of vasoconstriction and vasodilation?

A
  • At the start of exercise, the sympathetic nervous system causes vasoconstriction, thus the conditions are anaerobic at the start.
  • With sufficient oxygen levels, the conditions become aerobic.
  • Both types of respiration cause vasodilation.
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38
Q

what is the major difference between diffusion of carbon dioxide and of oxygen? and what does this mean in terms of pressure differences?

A
  • carbon dioxide can diffuse about 20 times as rapidly as oxygen
  • therefore, the pressure differences required to cause carbon dioxide diffusion are far less than the pressure differences required to cause oxygen diffusion
  • only a 5 mmHg pressure difference causes all the required carbon dioxide diffusion out of the pulmonary capillaries into the alveoli
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39
Q

what is the usual oxygen saturation of systemic arterial and venous blood?

A
  • The usual oxygen saturation of systemic arterial blood averages 97%.
  • The usual oxygen saturation of systemic venous blood averages 75%.
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40
Q

how many grams of Hb is there in each 100ml of blood? and how much oxygen can each gram of Hb bind with?

A

15g

maximum of 1.34 ml of oxygen

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41
Q

how much oxygen is released into the tissues?

A
  • Normal arterial blood is 97% saturated; this is about 19.4 milliliters of oxygen per 100 milliliters of blood.
  • After the tissue capillaries, this amount is reduced to 14.4 milliliters (Po2 of 40 mm Hg, 75% saturated hemoglobin), 5 milliliters of oxygen delivered by each 100 milliliters of blood.
  • Haemoglobin still retains three-quarters of its oxygen.
  • Venous blood has a relatively large oxygen reserve, which can be mobilized if tissue oxygen demands increase.
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42
Q

how much oxygen is released into the tissues during exercise?

A

- The muscles use oxygen at a rapid rate lowering muscle interstitial PO2 (40 mmHg to 15 mm Hg).
- At this low pressure, only 4.4 milliliters of oxygen remain bound with the haemoglobin in each 100 milliliters of blood.
- 15 milliliters of oxygen is delivered to the tissues by each 100 milliliters of blood flow during exercise (5ml normally).

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43
Q

how big a change in PO2 causes large amount of extra oxygen to be released from the Hb?

A

a very small fall in PO2

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44
Q

what causes a shift to the right in the haemoglobin saturation against pressure of oxygen curve?

A
  1. increased hydrogen ions
  2. increased CO2
  3. increased temperature
  4. increased BPG (2,3-Bisphosphoglyceric acid)
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45
Q

how does BPG in the blood affect the haemoglobin saturation curve?

A

the normal BPG in the blood keeps the oxygen-haemoglobin dissociation curve shifted slightly to the right all the time

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46
Q

how is carbon dioxide transported?

A
  • most is transported as carbonic acid
  • some binds to regions of haemoglobin to form carbamino compounds
  • a small portion is transported in the dissolved state to the lungs
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47
Q

how does haemoglobin act as an acid-base buffer?

A

H+ + haemoglobin -> HHb

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48
Q

what’s the chloride shift? why is it important?

A

HCO3- diffuse out of the red cells into the plasma, while chloride ions diffuse into the red cells to take their place, a phenomenon called the chloride shift.
- this maintains the pH of red blood cell.

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49
Q

in addition to reacting with water, what does carbon dioxide also directly react with?

A
  • Carbon dioxide reacts directly with amine radicals of the haemoglobin molecule to form the compound carbaminohaemoglobin (CO2Hb).
  • This is a reversible reaction that occurs with a loose bond, so that the carbon dioxide is easily released into the alveoli.
50
Q

describe the Haldane effect

A

• Haldane Effect: binding of oxygen with hemoglobin tends to displace carbon dioxide from the blood. This is the opposite of Bohr effect.
• The Haldane effect results from the simple fact that the combination of oxygen with hemoglobin in the lungs causes the hemoglobin to become a stronger acid.
• This displaces carbon dioxide from the blood and into the alveoli in two ways:
1. The more highly acidic haemoglobin has less tendency to combine with carbon dioxide to form carbaminohemoglobin, thus displacing much of the carbon dioxide.
2. The increased acidity of the haemoglobin also causes it to release an excess of hydrogen ions:
 The H+ + HCO3- = carbonic acid
 Carbonic acid dissociates into water and carbon dioxide.
 The carbon dioxide is released from the blood into the alveoli and into the air.

51
Q

how does the transport capacity of the blood for carbon dioxide and oxygen differ? how does affect it affect resulting hypercapnia and hypoxia?

A

the transport capacity of the blood for carbon dioxide is more than three times that for oxygen, so that the resulting tissue hypercapnia is much less than the tissue hypoxia (after increased ventilation)

52
Q

what happens at very high levels of PCO2?

A

the excess CO2 begins to depress respiration rather than stimulate it

53
Q

what are the two types of acidosis and what are the causes and compensation?

A

Respiratory:
cause = increased PCO2
compensation = increased HCO3-

Metabolic:
cause = decreased HCO3-
compensation = decreased PCO2

54
Q

what are the two types of alkalosis and what are the causes and compensation?

A

Respiratory:
cause = decreased PCO2
compensation = decreased HCO3-

Metabolic:
cause = increased HCO3-

55
Q

how can there by a change in pH without having a change in gas partial pressures?

A

if the base excess (normally -2 to +2) is out of the normal range, the condition is metabolic instead of respiratory

56
Q

what causes increase and decease in base excess?

A

increase in base excess due to:

  • increased excretion of acid in the kidneys
  • increased retention of bicarbonate ions in the kidneys

decrease in base excess due to:

  • overproduction of acid
  • increased loss of bicarbonate ions in the kidneys
57
Q

what is asthma due to?

A

inflammation of the air passages in the lungs which affects the sensitivity of the nerve endings in the airways so they become easily irritated

58
Q

what is status asthmaticus?

A

a state of unremitting attacks

59
Q

when does most asthma onset?

A

the most frequent form has onset in children between ages 3-5 years and may worsen or improve during adolescence

60
Q

what are three characteristics of asthma?

A
  1. Airflow limitation - reversible spontaneously or with treatment
  2. Bronchial hyper-responsiveness – this is “easily triggered bronchospasm” as a result of a wide range of stimuli
  3. Inflammation of the bronchi - T lymphocytes, mast cells, eosinophils (plasma exudation), oedema, smooth muscle hypertrophy, matrix disposition, mucus plugging and epithelial damage.
61
Q

what’s chronic asthma?

A

inflammation accompanied by irreversible airflow limitation as a result of airway wall remodelling

62
Q

how can asthma be categorised?

A

Atopic (extrinsic) – implying a definite external cause:
- Type I IgE-mediated hypersensitivity reaction.
- The disease usually begins in childhood and is triggered by environmental allergens.
- A positive family history of asthma is common, and a skin test with the offending antigen in these patients results in an immediate wheal-and-flare reaction.
- Atopic asthma may also be diagnosed based on evidence of allergen sensitisation by serum radioallergosorbent tests (called RAST), which identify the presence of IgE specific for a panel of allergens.
- Often seen in patients with family history of allergic rhinitis (eczema).

Non-atopic (intrinsic) – when no causative agent can be identified:
- These individuals with asthma do not have evidence of allergen sensitisation.
- Skin test results are usually negative.
- A positive family history of asthma is less common in these patients.
- Respiratory infections due to viruses are common triggers in non-atopic asthma. In these patients hyper irritability of the bronchial tree probably underlies their asthma.

63
Q

what is drug-induced asthma?

A

Aspirin-sensitive asthma:
occurs in individuals with recurrent rhinitis and nasal polyps
o These individuals are sensitive to aspirin as well as NSAIDS, and they experience not only asthmatic attacks but also urticaria.
o It is probable that aspirin triggers asthma in these patients by inhibiting the cyclooxygenase pathway of arachidonic acid metabolism without affecting the lipoxygenase route, thus tipping the balance toward elaboration of the bronchoconstrictor leukotrienes.

Propranolol:
o This is a sympatholytic non-selective beta blocker (antagonist).
o Sympatholytic: inhibits postganglionic functioning of sympathetic nervous system. In this case, this is achieved through blocking beta adrenergic receptors.
o Used to treat hypertension, anxiety and panic.
o These can trigger an asthma attack.

64
Q

what is occupational asthma?

A

- This form of asthma is stimulated by fumes, organic and chemical dusts, gases, and other chemicals.
- Minute quantities of chemicals are required to induce the attack, which usually occurs after repeated exposure.
- The underlying mechanisms vary according to stimulus and include type I hypersensitivity reactions, direct release of bronchoconstrictor substances, and hypersensitivity responses of unknown origin.

65
Q

what is atopy?

A

described as a group of disorders that appear to run in families, have characteristic sealing skin reactions to common allergens in the environment and to have circulating allergen-specific IgE

66
Q

how are genetics involved in asthma?

A

genes controlling production of cytokines IL-3,4,5,9,13 and GM-CSF - in turn affect mast and eosinophil development and longevity as well as IgE production.

67
Q

describe allergen-induced asthma (atopic asthma)

A

Inhalation of allergen by atopic asthmatic individuals leads to the development of different types of reactions:

1) Immediate asthma (early reaction):
 Airflow limitation begins within minutes of contact with the allergen, reaches its maximum in 15-20 minutes and subsides by 1 hour.

2) Dual and late phase reactions:
 This follows an immediate reaction.
 Many asthmatics develop a more prolonged and sustained attack of airflow limitation which responds less well to inhalation of bronchodilators such as salbutamol.

3) Isolated late phase reactions:
 Occurs with no preceding immediate response.
 After inhalation of some occupational sensitisers such as isocyanates.

68
Q

describe the initial sensitisation to an inhaled allergen

A

• In the airways, the scene for the reaction is set by initial sensitisation to inhaled allergens, which stimulate induction of Th2 cells.
• Th2 cells secrete cytokines that promote allergic inflammation and stimulate B cells to produce IgE and other antibodies.
• These include:
- IL-4, which stimulates the production of IgE by B cells.
- IL-5, which is a eosinophil chemotactic agent.
- IL-13, which stimulate mucus secretion from bronchial submucosal glands and also promote IgE production by B cells.

SENSITISATION:

  1. The Fc part of IgE binds to FcεR on mast cells/ basophils, exposing its variable region. This IgE loading takes 10-15 days.
  2. This is the SENSITISATION PHASE as the mast cells/ basophils are ready to work the next time the pollen appears.
  3. When the antigen reappears, they will come into contact with sensitised (IgE-loaded) mast cells and stimulate it and cause an initial phase reaction and a secondary reaction.
69
Q

describe the initial phase reaction

- effects of histamine

A
  1. Upon stimulation, the mast cells undergo degranulation, secreting preformed products (primary mediators). These include histamine, proteases, neutrophil chemotactic factor and eosinophil chemotactic factor.
  2. The proteases will do two things:
    • Further tissue damage, causing the release of more inflammation mediators.
    • Convert C3 and C5 into C3a and C5a which will bind to the receptors on the mast cells, thus simulating the mast cells further.
  3. The histamine has the following effects:
    • Vasodilation
    • Increased vascular permeability leading to partial edema in the area.
    • Spasmatogenic: histamine receptors are found on the smooth muscle lining of the various tracts. Histamine causes them to contract.
    • Increasing glandular secretions, causing luminal obstruction.
    • Overall, histamine causes narrowing of the lumen of the tract.
70
Q

describe the secondary reaction

- what do leukotrienes do

A
  1. This phase largely consists of inflammation with recruitment of leukocytes.
  2. Upon stimulation, the nucleus of the mast cell is activated, leading to protein synthesis of cytokines.
  3. These small, soluble proteins (cytokines) are released by the mast cell (and epithelial cells) and they act as signaling molecules.
  4. The cytokines are termed secondary mediators as they are not preformed.
  5. Two important cytokines are secreted by mast cells and epithelial cells: IL-3 and IL-5, which are chemotactic agents for eosinophils. IL-5 and IL-3 are also produced by Th2.
  6. The second wave of mediators stimulates the late reaction.
     Eotaxin - produced by airway epithelial cells, potent chemoattractant and activator of eosinophils.
     Major basic protein (MBP) of eosinophils causes epithelial damage and more airway constriction.
  7. Also, the mast cell secretes leukotrienes, which attract neutrophils.
  8. Eosinophils secrete their granular contents: histaminases (reducing inflammation) and enzymes that destroy leukotrienes (reducing attraction of neutrophils).
    • Many mediators have been implicated in the asthmatic response:
  9. Leukotrienes C4, D4, and E4: extremely potent mediators that cause prolonged bronchoconstriction as well as increased vascular permeability and increased mucus secretion.
  10. Acetylcholine: released from intrapulmonary motor nerves, which can cause airway smooth muscle constriction by directly stimulating muscarinic receptors.
71
Q

describe how ‘airway remodelling’ occurs over time

A
  1. Hypertrophy and hyperplasia of bronchial smooth muscle:
     Hyperplasia of the helical bands of airway smooth muscle.
     Smooth muscle also alters in function to contract more easily and stay contracted because of a change in actin-myosin cross-link cycling.
     These changes allow asthmatic airways to contract too much and too easily. (Muscular Bronchoconstriction/Bronchospasm)
  2. Epithelial injury:
     In the conducting airways there is loss of ciliated columnar cells into the lumen.
     Metaplasia occurs with a resultant increase in number and activity of mucus-secreting goblet cells.
  3. Increased airway vascularity.
  4. Increased subepithelial mucus gland hypertrophy/hyperplasia.
  5. Overall thickening of airway wall.
  6. Basement membrane is thickened due to subepithelial fibrosis with deposition of types III and V collagen below the true basement membrane.
72
Q

what can mast cells be stimulated by?

A
  1. Cross-linking of loaded IgE by multivalent antigens.
  2. C3a, C4a, C5a (mast cells have receptors for these).
  3. Drugs: codine and morphine.
  4. Venoms such as that from a bee sting.
73
Q

what are Curschmann spirals?

A
  • spiral shaped mucus plugs
  • contain whorls of shed epithelium

These result either from:

  • mucus plugging in subepithelial mucous gland ducts which later become extruded
  • plugs in bronchioles
74
Q

what are Charcot-Leyden crystals?

A

these are collections of crystalloid made up of a eosinophil lysophospholipase binding protein called galectin-10

75
Q

how long can status asthamticus persist for?

A

days and even weeks

76
Q

what is the clinical diagnosis (of status asthamticus) aided by?

A

- An increase in airflow obstruction
- Difficulty with exhalation (prolonged expiration, wheeze)
- Elevated eosinophil count in the peripheral blood and the finding of eosinophils
- Curschmann spirals
- Charcot-Leyden crystals in the sputum (atopic asthma)

77
Q

how do you diagnose asthma?

A

Compatible clinical history plus either/or:
- FEV1 ≥ 15% (and 200 ml) increase following administration of a bronchodilator/trial of corticosteroids.
- 20% diurnal (daily) variation on ≥ 3 days in a week for 2 weeks on PEF diary.
- FEV1 ≥ 15% decrease after 6 mins of exercise.

78
Q

what are the two categories of anti-asthma drugs? and what do they do?

A

- Bronchodilators - reverse the bronchospasm of the immediate phase
- Anti-inflammatory agents. Bronchodilators; anti-inflammatory agents inhibit or prevent the inflammatory components of both phases

79
Q

what bronchodilators are there?

A
  • B2-adrenergic receptor agonists - salbutamol
  • xanthine drugs - theophylline
  • muscarinic receptor antagonists - ipratropium
  • cysteinyl leukotriene receptor antagonists - montelucast
80
Q

B2-adrenergic receptor agonists

  • primary effect
  • other effects
  • categories
  • side-effects
A

β2 –adrenergic receptor agonists – Salbutamol/ Salmetrol:
• Their primary effect in asthma is to dilate the bronchi by direct action on the β2-adrenergic receptors of smooth muscle.
• They also inhibit mediator release from mast cells and TNF-α release from monocytes
• They increase mucus clearance by an action on cilia.

Two categories of β2-adrenergic receptor agonists are used in asthma:
Short-acting agents: Salbutamol
 - Given by inhalation
 - The maximum effect occurs within 30 minutes and the duration of action is 3-5 hours.
 - They are usually used on an ‘as needed’ basis to control symptoms.

Longer-acting agents: Salmetrol
 - These are given by inhalation.
 - The duration of action is 8-12 hours.
 - They are not used ‘as needed’ but are given regularly, twice daily, as adjunctive therapy in patients whose asthma is inadequately controlled by glucocorticoids.

Side Effects:
 - Tremor
 - Tachycardia
 - Cardiac dysrhythmia

81
Q

xanthine drugs - theophylline

  • what does it do
  • down side
  • side-effects
A
  • Acts as an inhibitor of phosphodiesterase, with resultant increase in cAMP – Causing muscle relaxation.
  • They are more likely to cause side effects and have a less favourable risk: benefit ratio.

• Unwanted effects:
 - CNS: stimulant (tremor, sleep disturbance)
 - Cardiovascular (stimulate heart, vasodilation)
 - GI tract (anorexia, nausea, vomiting)

82
Q

muscarinic receptor antagonist - ipratropium

  • action
  • benefit
A
  • Blocks actions of acetylcholine at receptor in parasympathetic nervous system.
  • Low levels of acetylcholine released from cholinergic nerves in airways.
  • Few muscarinic receptors activated.
  • Inhibit elevated mucus secretion in asthma and cause bronchodilation.
  • Well tolerated.
83
Q

cysteinyl leukotriene receptor antagonist

  • action
  • side effects
A
  • Prevent exercise-induced asthma and decrease both early and late responses to inhaled allergen.
  • Their action is additive with β2-adrenoceptor agonists.
  • They also reduce sputum eosinophilia.
  • Act at cysteinyl-leukotriene receptors - on bronchiole smooth muscle cells – blocking C4, D4.
  • Prevent actions of bronchial spasmogens.
  • Stimulate mucus secretion.

• Side Effects:
 - Headache
 - Gastrointestinal disturbances

84
Q

how are anti-inflammatory agents usually given? and how long does the full effect usually take?

A

by inhalation

a day or two

85
Q

what is an anti-inflammatory agent?

A

glucocorticoids

86
Q

glucocorticoids

  • what are they
  • what do they do
  • what are they used for
  • how do they work
A
  • They are not bronchodilators.
  • They prevent the progression of chronic asthma.
  • They are used as prophylactic treatment for asthma.
  • They are effective in acute severe asthma.
  • They decrease formation of cytokines in particular the Th2 cytokines that recruit and activate eosinophils (IL-5)
  • They are responsible for promoting the production of IgE and the expression of IgE receptors.
  • Glucocorticoids also inhibit the generation of some (PGE2 and PGI2) vasodilators.
Glucocorticoids:
Reduce production of:
	- Cytokines
	- Spasmogens (LTC4, LTD4)
	- Leucocyte chemotaxins (LTB4, PAF)
 Therefore reduce:
	- Bronchospasm
    - Recruitment and activation of inflammatory cells
87
Q

what is the mechanism of glucocorticoid action?

A 
- 	Enter cells
- 	Bind to intracellular receptors in cytoplasm 
     -GRα
     -GRβ
- 	Receptor complex move to nucleus
- 	Binds to DNA in nucleus
- 	Alters gene transcription
- 	E.g. induction of lipocortin
- 	E.g. repression of IL-3
88
Q

what is IL-3?

A

the cytokine that regulates mast cell production

89
Q

side effects of glucocorticoids?

A
  • oral candidas
  • sore throat
  • croaky voice
90
Q

how many patients non-adherent?

A

estimated that 40-50% of all patients

91
Q

what are systemic biases in risk perception?

A
  • Compression: overestimate low risks, underestimate high ones.
  • Miscalibration: overestimate accuracy of own knowledge.
  • Availability: overestimate notorious risks.
  • Optimism: underestimate personal susceptibility.
92
Q

what’s a psychosomatic disorder? which diseases are psychosomatic?

A
  • Psychosomatic means mind (psyche) and body (soma)
  • A psychosomatic disorder is a disease which involves both mind and body
  • Some physical diseases are thought to be particularly prone to be made worse by mental factors such as stress and anxiety
  • Your current mental state can affect how bad a physical disease is at any given time

Which diseases are psychosomatic?
To an extent, most diseases are psychosomatic – involving both mind and body
- There is a mental aspect to every physical disease
- There can be physical effects from mental illness
However, the term psychosomatic disorder is mainly used to mean ‘a physical disease that is thought to be caused, or made worse, by mental factors’

93
Q

what are the pulmonary blood vessels?

A
  • The lungs are supplied with deoxygenated blood by the paired pulmonary arteries
  • Once the blood has received oxygenation, it leaves the lungs via four pulmonary veins (two for each lung)
  • The bronchi, lung roots, visceral pleura and supporting lung tissues require an extra nutritive blood supply – this is delivered by the bronchial arteries, which arise from the descending aorta
  • The bronchial veins provide venous drainage – the right bronchial vein drains into the azygous vein, whilst the left drains into the accessory hemiazygos vein
94
Q

what is the respiratory mucosa and submucosa adapted to do?

A

warm and moisten the air and to trap particles in mucous

95
Q

what is the respiratory mucosa made up of? what does it do?

A
  • the respiratory mucosa is made up of the epithelium and supporting lamina propria
  • the epithelium is tall columnar pseudostratified with cilia and goblet cells
  • the supporting lamina propria underneath the epithelium contains elastin, that plays a role in the elastic recoil of the trachea during inspiration and expiration, together with blood vessels that warm the air
96
Q

what does the sub-mucosa contain? what does it do?

A
  • sub-mucosa contains glands which are mixed sero-mucous glands
  • th watery secretions from the serous glands humidify the inspired air
  • the mucous, together with mucous from the goblet cells traps particles from the air which are transported upwards towards the pharynx by the cilia on the epithelium
97
Q

histology of the respiratory tract

A

trachea: columnar pseudostratified epithelium with cilia and goblet cells
tertiary bronchi: columnar, not pseudostratified epithelium with very few goblet cells
bronchioles: ciliated columnar epithelium in larger bronchioles or non-ciliated in smaller bronchioles, no goblet cells, but have Clara cells (secrete one of the components of surfactant)
terminal bronchioles: ciliated cuboidal epithelium and Clara cells

98
Q

what are the two types of inhalers? what do they contain?

A

Blue inhalers:
- Normally contain a short-acting beta2-agonist, which widens the airways and makes breathing easier
Brown inhalers:
- Used twice or occasionally once a day to stop asthma symptoms occurring
- Contain inhaled steroid mediation, which works by reducing the inflammation and sensitivity of the airways

99
Q

what is prednisolone? how is it taken and why?

A
  • oral steroid medication - synthetic glucocorticoid
  • if you have serious worsening of asthma symptoms, your doctor may prescribe a brief course of oral steroids such as prednisolone
  • systemic anti-inflammatory steroid – after taking prednisolone orally, it is absorbed in the body, unlike inhaled steroids (anti-inflammatory asthma inhalers) that go straight to the lungs
100
Q

when are patients given long acting beta2-adrenergic receptor agonists?

A

they are given regularly, twice daily, as adjunctive therapy in patients whose asthma is inadequately controlled by glucocorticoids

101
Q

what can cause drug-induced asthma?

A

Propranolol:

  • this is a sympatholytic non-selective beta blocker (antagonist)
  • sympatholytic: inhibits postganglionic functioning of sympathetic nervous system – in this case, this is achieved through blocking beta adrenergic receptors
  • used to treat hypertension, anxiety and panic
  • these can trigger an asthma attack
102
Q

what is asthma an allergy?

A

yes it’s a type 1 hypersensitivity because IgE antibodies are produced

103
Q

propranolol

  • what is it
  • what’s the issue
  • what determines equilibrium of agonist and antagonist
  • what compete for the same site
A
  • antagonist for beta2-adrenoreceptors
  • trachea muscle will relax when you activate beta-adrenoceptors
  • doesn’t select between beta 1 and 2-adrenorecepotors
  • blocks effects of agonist
  • the higher the affinity of the antagonist and the higher the concentration of the antagonist, the less binding the agonist will get
  • propranolol and noradrenaline compete for the same sites
104
Q

what does equilibrium favour for most receptors, the active or inactive state?

A
  • Antagonist binds equally as well to the active state as the inactive state
  • When the agonist binds to the active receptor, it stabilises it, however, an agonist won’t stabilise the inactive state
  • Equilibrium favours inactive state when no agonist present
  • Equilibrium favours active state + agonist, over just active state
  • Equilibrium favours just inactive state, over inactive state + agonist
105
Q

what do partial agonists do?

A
  • Bind bit better to active state than the inactive state
  • End up with some of the receptor in its active state bound to partial agonist, but not as much as with the agonist
  • Still some bound to inactive state of receptor
106
Q

what is efficacy? what is efficacy of full agonist, antagonist and partial agonist?

A

how much you can activate the receptor when all binding sites are occupied

  • The magnitude of the effect a drug can achieve at saturation
  • The amount of activation a drug can produce once its occupied all the sites on a receptor
    e. g. may activate 50% of receptors but its bound to all the sites on the receptors
  • Full agonist = high efficacy
  • Antagonist = zero efficacy
  • Partial agonist = somewhere in between
107
Q

what is an inverse agonist?

A
  • Higher affinity for the inactive state than active state
  • They bind tightly to the inactive state so the receptor will be drawn to this state
  • Won’t look that different to competitive antagonism because most receptors in inactive state when agonist not present
  • They reduce spontaneous activity (competitive antagonists don’t affect spontaneous activity) – reduce the likelihood of the receptor spontaneously activating on its own
108
Q

what is potency?

A
  • The concentration of a drug it takes to cause a particular effect e.g. EC50 (effective concentration that gives 50% of the maximum response), IC50 (concentration that produces 50% inhibition – for antagonists)
109
Q

describe what causes inflammation in the lungs of asthma patients

A
  • Allergen
  • Binds to macrophage (antigen-presenting cell)
  • Activation of CD4+, Th2 lymphocyte
  • They generate interleukins 4 & 5
  • Interleukin 4 -> activate B lymphocyte -> plasma cell -> IgE antibody
  • Interleukin 5 -> activation of eosinophil & mast cells (IgE antibodies bind to these which causes them to release their content)
110
Q

central chemoreceptors are stimulated by what?

A
  • increase in PCO2

- not pH (H+ ions can’t get across into the brain to stimulate it), not hypoxia

111
Q

describe the activation of B2-adrenoceptors

A
  • B2 receptor – normally activated by NAdr or adrenaline, but also by synthetic B2 agonists
  • Binds to receptor
  • Protein undergoes conformational change
  • When this happens, it’s able to recognise G proteins
  • It interacts with the stimulatory G protein = Gs
  • It then activates adenylate cyclase (enzyme)
  • Which stimulates the production of cAMP from ATP
  • cAMP then activates inactive PKA to form activated PKA (protein kinase A = enzyme)
  • all active PKAs phosphorylate other proteins – so they go on to phosphorylate other proteins involved in smooth muscle contraction
  • which causes muscle relaxation
112
Q

what’s the most common side effect B2-agonists?

A

tremor - due to B2 receptors present in skeletal muscle - cause uncoordinated twitching of individual muscle fibres

113
Q

what is the mechanism of theophylline?

A
  • cAMP can be broken down by phosphodiesterase to AMP (the amount of cAMP that can accumulate in cells is limited by action of this enzyme)
  • but if you block this enzyme, you prevent the breakdown of cAMP, so you get more activated PKA etc. (same process as with B2 agonists)
114
Q

what are the actions of muscarinic antagonists?

A
  • Relax bronchial smooth muscle – bronchodilation
  • Inhibit elevated mucus secretion in asthma
  • May increase clearance of bronchial secretions

MUSCARINIC SYSTEM IN AIRWAYS (can get both muscarinic & nicotinic cholinergic receptors)
Airways are innervated by cholinergic neurones from the PNS – these release ACh from the nerve terminals onto the muscle, the ACh then interacts with muscarinic receptors on smooth muscle cells

115
Q

describe the muscarinic system in some patients with asthma

A

Evidence for increase ACh release
- Muscarinic receptors activated – hypersensitivity
- So, you get excessive ACh being released from nerve terminals
- Muscarinic receptors, through various mechanisms, increase calcium concentration inside cells
- Smooth muscle contraction
- Narrowed airways
Muscarinic antagonists:
- Prevent ACh from interacting and causing contraction
In some patients, the hypersensitivity of muscarinic receptors is the main problem so these would work well

116
Q

what is the process of leukotriene synthesis?

A

Phospholipids -> phospholipase A2 cleaves phospholipids to produce arachidonic acid
-> 5-lipoxygenase produces 5-HPETE -> leukotrienes
Or
->cyclo-oxygenase produces cyclic endoperoxides -> prostaglandins (bronchoconstriction, vasodilation)

117
Q

how does aspirin-induced asthma work?

A

Aspirin-induced asthma: aspirin blocks cyclo-oxygenase, which means all arachidonic acid is converted to leukotrienes, so you get excessive leukotrienes – antagonist blocks the receptors

118
Q

what different glucocorticoids are there?

A
  • Beclomethasone diproprionate
  • Budesonide
  • Fluticasone propionate
  • Occasionally prednisolone or hydrocortisone
119
Q

what’s the mechanism of glucocorticoids?

A
  • Glucocorticoids are lipid-soluble – they pass through the membrane
  • Bind to glucocorticoid receptors located in the cytoplasm – GRalpha, GRbeta
  • These receptors dimerise
  • Then the dimerised receptors can pass through the nuclear membrane into the nucleus
  • There, they bind to DNA – promoter points – and they influence the transcription of DNA
  • They change the amount of mRNA produced for different proteins – some may be increased, some decreased – e.g. induction of lipocortin (inhibits activity of phospholipase A2, so prevents phospholipids being broken down and producing leukotrienes and prostaglandins)  repression of IL-3
120
Q

summary of drug actions?

A
  • IgE antibody – for allergic asthma - omalizumab - targets and blocks IgE
  • Mast cell stabiliser
  • Bronchodilators – early phase responses
  • Anti-inflammatory – late phase responses

Medicine Sem 2 (10 decks)

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