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FBS2 > Physiology and Pharmacology of Systems > Flashcards

Physiology and Pharmacology of Systems Flashcards

1
Q

What are the pO2, haemoglobin O2 binding sites saturation, O2 content, pCO2 and CO2 content of venous blood?

A 
pO2 = 40 mmHg
Haemoglobin O2 binding sites saturation = 75%
O2 content = 150 ml/L
pCO2 = 46 mmHg
CO2 content = 520 ml/L
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2
Q

What is the pressure in the vena cavae?

A

3-8 mmHg

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3
Q

What do the P, QRS and T segments represent?

A

P: atrial contraction
QRS: ventricular contraction
T: ventricular relaxation

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4
Q

What are the differences between APs in the SA node and in other areas of the heart?

A

SA node: pacemaker currents due to funny channels (If) + T-type Ca2+ channels–> reaching of threshold triggers Ca2+ entry through L-type Ca channels –> depolarization –> repolarization through K+ loss
Other areas: fast Na+ entry –> Ca2+ entry through L-type provides plateau –> K+ loss provides repolarization

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5
Q

What is the diffusion conduction speed in the atria, AV node, ventricles and from endocardium to epicardium?

A

Atria: 1 m/sec
AV node: 0.05 m/sec
Ventricular bundles: 4 m/sec
Endo to epi: 0.3 m/sec

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6
Q

What are the end diastolic and end systolic volumes?

A

End diastolic: 120 ml

End systolic: 50 ml

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7
Q

How do preload, afterload and ANS influence the frank-starling curve?

A

Increased preload: shifts up
Increased afterload: shifts down
SNS (beta1 receptors): shifts up
PNS (muscarinic): shifts down

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8
Q

What are the pO2, haemoglobin O2 binding sites saturation, O2 content, pCO2 and CO2 content of systemic arterious blood?

A 
pO2 = 100 mmHg
Haemoglobin O2 binding sites saturation = 97%
O2 content = 200 ml/L
pCO2 = 40 mmHg
CO2 content = 480 ml/L
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9
Q

What are the formulas for MAP?

A 
MAP = BP*TPR
MAP = diastolic + (systolic-diastolic)/3
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10
Q

What is the incisura in pulse pressure due to?

A

Closure of aortic valve

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11
Q

What is the microcirculation?

A

Terminal arterioles, capillaries and post-capillary venules

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12
Q

What is the effect of orthostasis on CVP?

A

Blood pools in veins below the heart –> reduction in CVP and CO

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13
Q

How is the vascular system controlled by ANS?

A

SNS: vasocontriction (alpha1 receptors) in splanchnic, renal, cutaneous and muscle beds
ANS: vasodilation (muscarinic and NANC) in salivary glands, pancreas, intestinal mucosa, penis

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14
Q

Which stimuli lead to the release of NO by the endothelium?

A

Bradykinin, ATP, histamine, CO2, H+, ACh and blood flow

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15
Q

What are the actions of prostacyclin (PGI2) and endothelin?

A

PGI2: inhibits platelet aggregation
endothelin: vasoconstrictor at ETa receptors

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16
Q

How do vasodilating substances in the blood lead to SM relaxation?

A

sensed by receptors in endothelial cells:
NO-mediated:
1. increase in Ca2+ –> eNOS activation –> production of NO from L-arginine
2. NO diffuses into smooth muscle
3. Increase in cGMP –> decrease in Ca2+ –> relaxation
*increased flow directly activates eNOS
Hyperpolarization-mediated:
1. increase in Ca2+ –> Ca2+-activated K+ channels –> hyperpolarization
2. Hyperpolarization spreads through gap junctions to SM cells
3. decrease in Ca2+ in SM cells –> relaxation

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17
Q

How do vasoconstricting substances in the blood lead to SM constriction?

A

sensed by receptors in endothelial cells:

1. release of endothelin –> travels to SM cells –> contraction

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18
Q

Why does oxidative stress interfere with the ability of blood vessels to dilate?

A

Superoxide reacts with NO to form peroxynitrite

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19
Q

What are the cAMP mediated mechanisms of vasodilation?

A

Activation of beta2, PGI2 and adenosine receptors on vascular SMCs –> adenylate cyclase activation –> cAMP –> vasodilation

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20
Q

What is the action of EETS?

A

release by endothelium and activate K+ channels in SMCs –> vasodilation

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21
Q

What is autoregulation?

A

When blood flow in certain beds remains constant over a wide range of pressures due to myogenic response and effects of flow on local concentrations of metabolites

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22
Q

What is reactive hyperaemia?

A

When blood flow is occluded –> build up of metabolites –> vasodilation
Blood flow is restored –> wash out of metabolites –> return to original

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23
Q

Where are fenestrated and sinusoidal epithelia located?

A

Fenestrated: kidneys, joints, intestinal mucosa
Sinusoidal: liver, bone marrow and spleen

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24
Q

What does the reflection coefficient (sigma) represent?

A

Permeability of a substance; the higher the less permeable

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25
Q

What is the Starling equation and what are the normal values for feeding relaxed arterioles?

A

Described the net fluid movement:
Jv = (Pcap - Pint) - sigma(picap - piint)
Jv = (40 - 0) - sigma(27 - 10)

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26
Q

How does vasoconstriction affect hydrostatic capillary pressure?

A

Vasoconstriction leads to a decreased hydrostatic capillary pressure –> increased absorption of fluids from interstitium

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27
Q

What are lymphangions?

A

Afferent trunks of the lymphatic systems that run next to major blood vessels; contain smooth muscle and pacemaker cells that pump fluid forwards

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28
Q

What are the four things that directly influence cardiac output?

A

Preload, afterload, heart rate, contractility

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29
Q

What is compliance?

A

Change in volume given a change in pressure

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30
Q

What are the compensatory mechanisms activated by heart failure?

A
  1. Fall in BP –> decreased renal salt and water excretion –> increase in blood volume
  2. SNS and RAAS –> fluid retention, increased contractility and heart rate, and venoconstriction
  3. Greater venous blood volume and venoconstriction increases CVP
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31
Q

What is the effect of aterload on CO?

A

Initial decrease but then:

  1. More blood remains in heart –> increase EDV and pressure –> restoration of SV
  2. ANREP response (release of substances which increase calcium in myocytes)
  3. Depression of CO by the baroreceptor reflex
    * Therefore little effect on CO
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32
Q

How is cardiac contractility defined?

A

Strength of contraction; amount and rate of cardiac tension development, and the ability of the heart to eject a stroke volume at a given preload and afterload; mainly regulated by calcium concentration in myocytes

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33
Q

What are the effects of sympathetic and parasympathetic stimulants on pacemaker APs?

A

Symp: increases If, faster rate of depolarisation, faster heart rate
Parasymp: decreases If, opens KAch channels, slower rate of diastolic depolarisation, slower heart rate

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34
Q

What is the duration of a neuronal AP?

A

500 microseconds

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35
Q

What is the duration of a cardiac AP?

A

200-400 msec

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36
Q

How is calcium extruded from the cardiac cell?

A

Na/Ca exchanger in cell membrane

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37
Q

What is duration of the AP roughly equal to in the ECG?

A

QT interval

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38
Q

What is the normal range in humans for the QT interva;?

A

350-380 msec

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39
Q

What are the two theories behind the generation of a regular pulse in pacemaker cells?

A
  1. Membrane clock: cyclical changes in ionic currents

2. Calcium clock: cyclical release of Ca from intracellular stores

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40
Q

What is the action of ivabradine?

A

Block If channels

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41
Q

How does anisotropic conduction in the heart travel?

A

along fibers rather than across them

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42
Q

What does Q represent?

A

Depolarization of the septum (towards the atria)

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43
Q

What does S represent?

A

depolarization of the ventricles towards the atria

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44
Q

What does T represent?

A

Repolarisation of the ventricles (towards endocardium)

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45
Q

What does the PQ interval tell us?

A

Atrial conduction and AV nodal delay; pathology: AV block

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46
Q

What does the QRS interval tell us?

A

The ventricular conduction velocity; pathology: bundle branch block

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47
Q

What does the ST segment tell us?

A

Heterogeneity of ventricle polarisation; pathology: myocardial infarction

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48
Q

What does the QT segment tell us?

A

Ventricular AP duration; pathology: long QT segment

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49
Q

Which accessory protein regulates SERCA?

A

phospholamban (PLB)

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50
Q

What are chronotropy, ionotropy and lusitropy?

A

chronotropy: heart rate
ionotropy: strength of contraction
lusitropy: rate of relaxation

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51
Q

What are examples of positive and negative chronotropic agents?

A

positive: adrenaline and noradrenaline
negative: ACh, adenosine

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52
Q

What are examples of positive ionotropic and lusitropic agents?

A

beta1 receptor stimulators (adrenaline and noradrenaline)

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53
Q

Which are the targets for PKA phosphorylation in the cardiac cell?

A 
L-type Ca channels;
RYR2;
Pacemaker (membrane and ca clocks);
Phospholamban (PLB) and phospholemman (PLM);
Troponin I and myosin binding protein C
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54
Q

What does the integrated area bounded by a PV loop represent?

A

A measure of stroke work

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55
Q

How is the jugular venous pulse described and what are its waves and descents?

A

Biphasic:
A wave: atrial contraction;
X descent: atrial relaxation;
C wave: interruption of X descent cause by carotid pulse;
V wave: right atrial filling during ventricular systole and bulging of tricuspid valve;
Y descent: right atrial emptying during ventricular diastole, before contraction

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56
Q

How is the peripheral arterial pulse described and what are the factors that influence it?

A

Monophasic; influenced by: reflected waves, compliance, damping, interference and resonance

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57
Q

How do you measure CVP from jugular vein?

A

Needs to be <3 cm above manubriosternal angle when patient is at 45 degrees

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58
Q

How does the JVP look like in tricuspid stenosis?

A

A wave is enhanced and V wave is diminished

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59
Q

How does the JVP look like in tricuspid regurgitation?

A

V wave is enhanced and A wave is diminished

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60
Q

Which are the primary heart sounds?

A

S1: initiation of ventricular systole and AV closure, low frequency
S2: closure of semilunar valves, higher frequency and shorter

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61
Q

Which are the secondary heart sounds?

A

S3: opening of AV valves and rapid refilling
S4: atrial systole, only heard when EDP is raised

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62
Q

Which problems result in diastolic murmurs?

A

Mitral stenosis and aortic incompetence

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63
Q

Which problems result in systolic murmurs?

A

Aortic stenosis and mitral incompetence

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64
Q

What is the difference between internal and external respiration?

A

Internal respiration: exchange of gases between blood, interstitial fluid and cells
External respiration: exchange of gases between blood and external environment

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65
Q

What is Boyles law?

A

PV=constant; thus, decrease volume = increase in pressure

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66
Q

What is the intrapleural pressure at the resting end of expiration?

A
  • 5 cmH2O
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67
Q

How are transmural pressures calculated?

A

pressure differential of the inside compartment minus the outside compartment

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68
Q

What is the transmural/transpulmonary pressure at resting end of expiration?

A

0-(-5) = +5 cmH2O

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69
Q

What does a high transpulmonary pressure indicate?

A

Work breathing difficulty is increased

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70
Q

What is the tidal volume?

A

Amount of air moved in one respiratory cycle (approximately 500 ml)

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71
Q

Which lung volumes cannot be measured by spirometry?

A

Total lung capacity, residual volume and functional residual capacity

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72
Q

What is dead space?

A

airway volume with no gas exchange (approximately 150 ml)
Anatomic: all except alveoli and respiratory bronchioles
Physiologic: anatomic + area where gas exchange is dysfunctional

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73
Q

How do you calculate alveolar ventilation?

A

Minute ventilation - dead space ventilation per minute = 7500 - (150*15) = 5250 ml/min

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74
Q

What are elastic and airway resistance?

A

Elastic: resistance to stretch of lung tissue and the air-liquid interface lining the alveoli
Airway: resistance due to friction between layers of flowing air and between the air and the airway walls

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75
Q

How can airway resistance be calculated?

A

(alveolar pressure - mouth pressure)/ airflow at mouth

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76
Q

What determines airway resistance?

A

Laminar flow and turbulence

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77
Q

Which are the airway components that contribute most to RAW?

A

Medium size bronchi around generation 3-5

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78
Q

What are the two main factors causing variation in RAW?

A

Factors within the airways: smooth muscle tone, inclammation, hypertrophy of mucous glands
Pressure across airway wall: positive intrapleural pressure

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79
Q

Which factors lead to bronchoconstriction?

A
  1. Vagal efferents: inhibited by pulmonary stretch receptors and stimulated by airway irritant receptors
  2. NANC nerves: SP and neurokinins
  3. Histamine, prostaglandins, leukotrienes
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80
Q

Which factors lead to bronchodilation?

A
  1. CO2
  2. NANC nerves: NO and VIP
  3. beta-adrenergic agonists (adrenaline and salbutamol)
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81
Q

What is the dynamic compression of airways due to?

A

At forced expiration, airway pressure falls below intrapleular pressure –> thus, forced expiration becomes effort independent

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82
Q

How do we measure lung compliance?

A

change in lung volume/transpulmonary pressure

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83
Q

How can intrapleural pressure be measured?

A

Through oesophageal balloon

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84
Q

How is lung volume measured?

A

With spirometer

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85
Q

What is the shape of the static pressure - volume loop and what does it indicate?

A

sigmoidal, lung compliance is highest at tidal volume

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86
Q

How do ephysema, lung fibrosis and neonatal respiratory distress syndrome affect lung compliance?

A

ephysema: high compliance
fibrosis: low compliance
neonatal respiratory distress syndrome: low compliance

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87
Q

What is bronchiolitis?

A

Thick, narrow bronchioles with excess mucous

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88
Q

What is the equation of laPlace?

A

pressure = 2surface tension/ radius

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89
Q

What is surfactant?

A

Produced by type II alveolar cells, a mixture of phospholipids (phosphatidylcholine) and surfactant proteins –> lowers surface tension of alveolar lining fluid –> prevents collapse of small alveoli into big alveoli + increases compliance + reduces tendency to suck fluid into alveoli

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90
Q

What are examples of obstructive pulmonary diseases?

A

Asthma, COPD (emphysema + chronic bronchitis)

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91
Q

What are examples of restrictive pulmonary diseases?

A

fibrosis, respiratory muscle weakness, phrenic nerve damage

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92
Q

How do you measure RAW?

A

Body plethysmograph or spirometer (peak flow or FEV vs time or forced vital capacity)

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93
Q

What is the normal forced expiratory ratio (FEV1/FVC)?

A

more than 75%

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94
Q

How do obstructive and restrictive pulmonary diseases affect FEV1, FVC and the forced expiratory ratio?

A

Obstructive: FEV1 decreased a lot, FVC decreased or normal, FEV/FVC decreased
Restrictive: FEV1 decreased, FVC decreased, FEV/FVC normal

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95
Q

How do lung fibrosis and emphysema affect functional residual capacity?

A

Fibrosis: reduces
Emphysema: increases

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96
Q

What is Dalton’s law?

A

in a mixture of non-reacting gases, the total pressure exerted is equal to the sum of partial pressures of the individual gases

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97
Q

How do you calculate partial pressure of oxygen?

A

PO2 = fractional concentration (FO2) * Pb

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98
Q

What is Henry’s law?

A

concentration of dissolved gas = k*partial pressure

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99
Q

How do the solubility constants of N2, O2 and CO2 relate to each other?

A

CO2 is >20 times O2

O2 is around 2x N2

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100
Q

What is the water vapour pressure in the lungs?

A

6.3 kPa (47 mmHg)

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101
Q

How do you calculate PIO2?

A

(Pb - 6.3)*0.209 kPa

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102
Q

How do you calculate PAO2?

A

PIO2 - (PACO2/R)

R = CO2 production/O2 consumption, usually around 0.8

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103
Q

What are the values of PO2 and PCO2 in mixed expired air and alveolar gas?

A

Mixed expired: 16 and 3.5 pKa
Alveolar: 13.5 and 5.3 pKa
1 pKa = 7.5 mmHg

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104
Q

Why does CO2 equilibrate rapidly despite having a much lower pressure gradient than O2?

A

Diffuses at 85% rate of O2 (higher MW), however 23 times more soluble than O2 –> 23*0.85 = 20 times faster than O2

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105
Q

What is Fick and Graham’s law?

A

rate of transfer of gas through a sheet of tissue = A(P1-P2)/T
T = thickness

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106
Q

How do you calculate CO diffusing capacity?

A

DLCO = CO uptake from the lungs (VCO)/PACO

107
Q

How does congestive heart failure affect diffusion of gases?

A

Interstitial oedema –> increased thickness –> decreased uptake of gases from lung

108
Q

Which factors reduce DLCO?

A

Reduction in alveolar-capillary membrane area; increased thickness of alveolar-capillary membrane; anaemia

109
Q

Which factors increase DLCO?

A

increased pulmonary blood volume –> increased effective area; polycythaemia

110
Q

What is the resting O2 consumption?

A

250 ml/min

111
Q

What is the oxygen capacity of normal blood?

A

200 ml/l

112
Q

What is the concentration of Hb in normal blood?

A

150 g/l

113
Q

What is the PO2 of mixed venous blood?

A

5.3 kPa

114
Q

What is the normal oxygen content in venous blood?

A

150 ml/l

115
Q

How does acute altitude affect: O2 capacity of arterial blood, arterial oxygen content, arterial oxygen saturation of Hb?

A

O2 capacity of arterial blood: normal
arterial oxygen content: reduced
arterial oxygen saturation of Hb: reduced

116
Q

How does anemia affect: O2 capacity of arterial blood, arterial oxygen content, arterial oxygen saturation of Hb?

A

O2 capacity of arterial blood: reduced
arterial oxygen content: reduced
arterial oxygen saturation of Hb: normal

117
Q

What are the centres in the brain stem involved in the control of respiration?

A

Pons:
1. Pneumotaxic centre: inhibits inspiratory phase
2. Apneustic centre: prolongs inspiration
Medulla:
1. Ventral respiratory group (contains nucleus ambiguus and retroambigualis)
2. Dorsal respiratory group (within nucleus tractus solitarius)
3. Pre-botzinger complex (key of respiratory rhythmogenesis)
4. Botzinger complex

118
Q

What is the function of the DRG?

A

inspiratory neurones only, fire immediately prior to and during inspiration; receives input from lung chemoreceptors and mechanoreceptors (IX and X CN); inhibit expiratory neurones in VRG and pontine respiratory group (PRG)

119
Q

Through which structures does voluntary breathing affect respiratory muscles?

A

Pyramidal tracts

120
Q

Where are stretch receptors situated and what is their role?

A

Smooth muscle of bronchial walls, makes inspiration shorter and shallower, delays next inspiratory cycle

121
Q

What is the Hering-breuer inflation reflex?

A

inflation inhibits inspiration

122
Q

Where are juxtapulmonary receptors situated and what is their role?

A

alveolar/bronchial walls, close to capillaries; cause apnoea or rapid shallow breathing, fall in HR and BP, laryngeal constriction, relaxation of skeletal muscles; stimulated by: pulmonary oedema, pulmonary congestion, microembolisms, inflammatory mediators (histamine)

123
Q

Where are irritant receptors situated and what is their role?

A

Throughout airways between epithelial cells; in trachea lead to cough, in lower airways hyperapnoea, reflex bronchial and laryngeal constriction
Stimulated by: irritant gases, smoke and dust, inflammation, rapid large inflations and deflations, pulmonary congestion
*responsible for deep augmented breaths every 5-20 minutes

124
Q

Where are proprioceptive afferents situated and what is their role?

A

Respiratory muscle; shortening and load of respiratory muscles (except diaphragm)

125
Q

What are the functions of pain receptors in the lung, trigeminal region and larynx receptors and arterial baroreceptors?

A

Pain receptors: cause brief apnoea + increased breathing afterwards
trigeminal region and larynx receptors: apnoea or spam, heart + sneeze reflex
arterial baroreceptors: stimulation inhibits breathing

126
Q

How can you estimate the rate of metabolism?

A

CO2 production, O2 consumption and H+ production

127
Q

How do you calculate PalveolarCO2?

A

PACO2 = (rate of CO2 production)/alveolar ventilation

128
Q

How is the relationship between hypoxia and hypercapnia described?

A

Synergistic

129
Q

Where are the central chemoreceptors situated?

A

Ventrolateral surface of medulla, near the exit of CN IX and X; responsible for 80% of hypercapnic response

130
Q

Which molecules are impermeable to movement from the blood into CSF and which are?

A

Impermeable: H+ and HCO3-; permeable: O2 and CO2

131
Q

How is the pH of the interstitium lining the CSF cavity governed?

A

Diffusion of CO2 from blood and HCO3- from CSF

132
Q

What is the H+ concentration at the chemoreceptor proportional to?

A

PCO2 (from blood)/HCO3- (in CSF)

133
Q

What are central chemoreceptors primarily affected by?

A

Arterial pCO2

134
Q

Are the amounts of proteins in the CSF high or low? How does that reflect on changes in pH?

A

Low; no buffering of pH —> small changes in pCO2 lead to large changes in pH

135
Q

Is the central chemoreceptor response fast or slow?

A

Slow

136
Q

What is the adaptation mechanism of central chemoreceptors in prolonged hypercapnia and altitude?

A
  1. Prolonged hypercapnia: CSF pH returns to normal, ventilatory drive decreases —> chronic respiratory disease
  2. Altitude: CSF initially alkaline due to hypoxic drive, CSF returns to normal and drive increases
137
Q

Where are the peripheral chemoreceptors situated?

A

Aortic bodies on aortic arch, innervated by vagus; carotid body in bifurcation, innervated by glossopharyngeal

138
Q

What are the carotid bodies composed of?

A

Type I (glomus cells) —> rich in NTs; Type II (sheath cells) —> partly enclose type I

139
Q

What is the function of peripheral chemoreceptors?

A

Increased discharge upon increased PCO2 and H+ (20% of hypercapnic response) and decreased PO2

140
Q

What is Cheyne-Stokes respiration?

A

fast breathing for a period and then apnoea breaks; heart failure (marker of poor prognosis), stroke, altitude sickness

141
Q

What is central sleep apnoea?

A

Can’t breathe: neuromuscular (muscular dystrophy, phrenic nerve damage; won’t breathe: brainstem damage/disease (Curse of Ondine)

142
Q

What are the V/Q ratio in shunt and dead space effect?

A

Shunt: 0
Dead space effect: infinite
Normal: around 1

143
Q

Which veins contribute to a right to left shunt?

A

Bronchial veins and thebesian veins (drain the wall of the left ventricle)

144
Q

Which conditions contribute to an abnormal right to left shunt?

A

Collapse; consolidation; some congenital heart diseases (Fallot’s tetralogy)

145
Q

What is Fallot’s tetralogy?

A

Overriding aorta, pulmonary stenosis by infundibulum, right ventricular hypertrophy, ventricular septal defect

146
Q

Calculate the arterial O2 and CO2 contents in a circulation with a 20% shunt effect.

A

O2 content: 0.8200 + 0.2150 = 190 ml/l

CO2 content: 0.8480 + 0.2520 = 488 ml/l

147
Q

How do rises and falls in O2 and CO2 contents affect PO2 and PCO2?

A

Moderate rise in CO2 content –> very small rise in PCO2

Moderate fall in O2 content –> large fall in PO2

148
Q

What is the effect of increased ventilation in right to left shunt?

A

Low arterial PO2 and high arterial PCO2 –> stimulation of chemoreceptors –> increased ventilation –> ventilated areas lose more CO2 but gain little extra O2 (as haemoglobin is already saturated), shunt blood is unaffected
Result: low PaO2, normal or low PaCO2

149
Q

What is the resulting picture in diseases with a variety of V/Q mismatches?

A

Low PO2 and high PCO2 –> peripheral and central chemoreceptor stimulation –> increased ventilation –> low O2 content, low PO2, low or normal CO2 content, low or normal PCO2

150
Q

Why do high V/Q areas not compensate for low V/Q areas?

A

More blood tends to come from low V/Q areas, raising local PO2 in high V/Q areas does little to increase oxygen content

151
Q

How can giving oxygen help you distinguish between right to left shunt and perfusion mismatching?

A

Improvement: perfusion mismatching

No improvement: right to left shunt

152
Q

How does V/Q vary between the top and bottom of the lung?

A

V/Q is higher at the top than the bottom

153
Q

Which mechanisms account for PO2 A-a differences?

A

physiological shunts and regional differences in V/Q in the lungs

154
Q

What is hypoxic pulmonary vasoconstriction?

A

Pulmonary blood vessels constrict in response to hypoxia —> improves V/Q matching (helpful if regional, causes RV hypertension if global)

155
Q

How do you assess V/Q mismatching?

A
  1. Isotope ventilation and perfusion scans
  2. Measure alveolar dead space and shunt effect using inert gases, modified Bohr and shunt equations
  3. From “A-a” PO2 gradient. Should only be a 5-10mmHg difference, upper limit is 15.
156
Q

Which five mechanisms lead to arterial hypoxia?

A
  1. Hypoventilation
  2. Low inspired PO2
  3. Right to left shunt
  4. Diffusion impairment
  5. V/Q mismatching
    * only hypoventilation leads to high PaCO2
    * 3,4,5 lead to increased A-a PO2 gradient
157
Q

What are the arterial and venous pressures in the head and feet of a supine and standing person?

A

Supine:
1. Arterial pressure: slightly lower than aortic (90-96 mmHg)
2. Venous pressure: slightly higher than CVP (4 mmHg –> 10 mmHg)
Standing:
1. Arterial pressure: 60 mmHg in head and 186 mmHg in feet
2. Venous pressure: 0 mmHg and subatmospheric outside and inside cranium, 100 mmHg in feet, CVP = 1 mmHg

158
Q

Which are the three mechanisms limiting the effect of orthostasis?

A
  1. Decreased SV and CO, blood flow to the brain and MABP in the upper part of the body –> activation of baro and volume receptors –> increase HR, vasoconstriction and TPR
  2. Arteriolar constriction: reflex sympathetic vasoconstriction via baroreceptors and local sympathetic axon reflex (veno-arteriolar axon reflex)
  3. Skeletal muscle pumping –> aids venous return
159
Q

What are varicose veins due to?

A

valve failure in tributary superficial veins

160
Q

Describe what happens in the veins inside and outside the cranium upon standing up

A

Outside cranium: veins collapse, pressure falls from 4 to 0 mmHg, because pressure in veins falls less than in arteries (100 –> 60), arteriovenous pressure gradient driving cerebral perfusion falls
Inside cranium: veins do not collapse –> pressure falls to -10 mmHg, same situation
Result: cerebral flow decreases by 20%

161
Q

What does prolonged standing lead to?

A

Sudden fall in TPR (vasodilation) and heart rate –> vasovagal syncope (steep fall in BP and cerebral blood flow)

162
Q

How do you calculate O2 consumption?

A

cardiac output*(arterial-mixed venous O2 content)

163
Q

How do you calculate arterial O2 content?

A

Hb concentrationO2 saturation1.34

164
Q

What is the main factor determining VO2 max?

A

maximum cardiac output

165
Q

How does dynamic exercise affect CO, SV, HR, BP and TPR?

A 
CO: increased
SV: increased
HR: increased
BP: systolic is increased, diastolic is normal or decreased, mean BP moderate increase
TPR: decreases
166
Q

How does BP change in isometric exercise and what is this partially due to?

A

Systolic and diastolic BP both rise, more than in dynamic exercise; increased TPR due to compression of blood vessels in contracting muscle

167
Q

What is circulatory shock?

A

generalised inadequacy of blood flow through the body; caused by haemorrhage, burns, severe vomiting, diarrhoea, acute MI, anaphylaxis, sepsis

168
Q

How does WHO classify haemorrhage?

A

Minimal <15%
Mild: 20-30%
Moderate: 30-40%
Severe >50%

169
Q

What are the immediate compensatory mechanisms for haemorrhage?

A
  1. Venoconstriction
  2. Reflex responses: increased HR and force, peripheral vasoconstriction of skin, gut, kidney and muscle, increased sweating
  3. CNS ischaemic response: powerful peripheral vasoconstriction
  4. Activation of RAAS
170
Q

How does moderate haemorrhage affect BP, CO, TPR and pulse pressure?

A

BP: normal
CO: low
TPR: high
Pulse pressure: low

171
Q

How does internal transfusion work?

A

Capillary hydrostatic pressure is reduced due to vasoconstriction and fall in venous pressure –> fluid reabsorption from interstitium into plasma

172
Q

What are the renal mechanisms to restore blood volume?

A

Decreased BP and blood volume –> sensed by:

  1. Baroreceptors –> brain stem and hypothalamus –> increased ADH and sympathetic renal nerve activity –> decreased diuresis and increased renin –> Na+ and water reabsorption
  2. Decreased atrial stretch –> decreased ANP –> increased Na+ and water reabsorption
173
Q

How long does it take to restore blood volume in mild blood loss (25%)? What about Hb, plasma proteins and reticulocyte count?

A

blood volume: 1-3 days;
Hb concentration: normal immediately after haemorrhage, haemodilution leads to fall, up to 6 weeks for full recovery
Plasma proteins: 1 week
Reticulocytes: up to 6 weeks

174
Q

What is progressive shock?

A

Where blood loss exceeds 30%, CO may initially improve (reversible shock) before a progressive decline (irreversible shock) unless transfusion is performed in golden hour

175
Q

What are the cardiovascular effects of ageing?

A
  1. arteriosclerosis (hardening of arteries: increased collagen and decreased elastin)
  2. Rise in systolic BP and fall in diastolic BP (increased TPR due to increased symp activity and decreased NO)
  3. Reduced baroreflex sensitivity
  4. Impaired cardiac performance during exercise
176
Q

How does the speed of the pulse wave change in ageing?

A

Pulse wave is faster; forward + reflected pressure waves are higher

177
Q

What are the cardiac changes in ageing?

A
  1. Maximum HR falls
  2. Fall in cardiac contractility reduces SV
    Due to decreased beta1 receptor activation and loss of myocytes
178
Q

What is the shape of a log drug concentration vs response curve?

A

sigmoidal

179
Q

What is the EC50 of a drug used to quantify?

A

Potency of the drug

180
Q

How is affinity of a drug for its receptor quantified?

A

By its Kd (molar concentration of a drug required to occupy 50% of the receptors at equilibrium)

181
Q

What is efficacy?

A

The ability of a drug to activate its receptor

182
Q

What are examples of reversible competitive antagonists?

A

Pancuronium (muscle relaxant), terfenadine (antihistamine), propanolol

183
Q

What is the pA2 of an antagonist?

A

The negative logarithm of the molar concentration of antagonist that necessitates that you double the agonist concentration to produce the same response (dose ratio = 2.0); measure of the affinity of the antagonist

184
Q

What are the three types of pharmacological receptors?

A

Physiological receptors, other proteins (enzymes, ion channels), nucleic acids

185
Q

What is pharmacodynamics and what is pharmacokinetics?

A

Pharmacodynamics: what the drug does to the body
Pharmacokinetics: what the body does to the drug

186
Q

What are the three names of a drug?

A

Proprietary name: dispirin CV
Common name: aspirin
Chemical name: acetylsalicyclic acid

187
Q

What are the common name and mechanism of prozac ?

A

Fluoxetine; blocks 5-HT uptake –> SSRI

188
Q

How long does the preclinical phase usually take?

A

5-10 years

189
Q

What are phase 0, I, II and III of drug development?

A

Phase 0: subtherapeutic dosing in human subjects, good pharmacokinetic information + tests on humanised animals and tissues
Phase I: 20-80 healthy volunteers, side-effects and safety, tolerability and dose-finding
Phase II: 100-300 patient volunteers, side-effects and safety, effectiveness
Phase III: 1000-3000 patient volunteers, side-effects, safety and effectiveness + comparison with currently available medicines

190
Q

How long do phase I-III usually take?

A

6-10 years, 500-1000m pounds

191
Q

What happens after Phase III?

A

Registration with MHRA, EMA, FDA

Phase IV: post-registration studies, different populations, long-term safety

192
Q

What are the three reasons of drug development failure?

A

Safety, efficacy (most important), economics

193
Q

What does an acceptable benefit:risk ratio depend on?

A

Efficacy, toxicity, disease

194
Q

Why does Seldane cause fatal arrhythmias?

A

Terfenadine is metabolised by CYP3A4
CYP3A4 inhibition –> blockage of cardiac Ikr channel –> long Q-T interval –> increased likelihood of torsades de point
*removal of terfenadine drugs and introduction of fexofenadine

195
Q

Why does Tysabri cause fatal brain damage?

A

Tysabri (natalizumab) is a humanised anti-VLA4 Ab Progressive multifocal leukoencephalopathy (PML) is caused by JCV; a common polyoma virus
PML occurs in severe immunosuppression.
VLA4 is essential for memory T-cell surveillance of the CNS

196
Q

Which are the determinants of mean arterial BP?

A

BP = COTPR
TPR is influenced by arterial tone
CO = HRSV
SV is influenced by:
1. Afterload –> decreases SV
2. Cardiac contractility
3. CVP-preload (affected by blood volume and venous capacitance)
*All except blood volume are short-term adjusted by baroreceptor reflex
*blood volume: long-term, adjusted by kidneys

197
Q

Where are baroreceptors situated and how are they stimulated?

A

Carotid sinus (more important) and aortic arch; responsive to stretch (mechanoreceptors)

198
Q

At which range of BP are baroreceptors most sensitive?

A

80-150 mmHg

199
Q

What are the effects of blood volume on Na+ excretion?

A

increased blood volume:

  1. increased atrial stretch: cardiopulmonary receptors are activated –> decreased SNS to kidneys –> decreased RAAS and increased Na+ excretion, increased ANP release –> increased Na+ excretion
  2. decreased RAAS –> decreased Na+ excretion
  3. increased BP: increased pressure natriuresis + decreased RAAS
200
Q

What is the principle of the Guyton’s model?

A

small rise in blood pressure drives increased sodium excretion

201
Q

What is the neurogenic model of blood pressure control?

A

SNS can mediate or contribute to the long term control of BP

202
Q

How much can 1 g of Hb combine with ml of O2?

A

max of 1.34 ml of O2

203
Q

What is the normal arterial PO2?

A

12.5 kPa (100 mmHg)

204
Q

What is the effect of anemia on venous and tissue PO2?

A

Will be lower (3.6 kPa), as tissues need to extract same amount 50 ml/l; tissue PO2 will be low as well –> hypoxia

205
Q

What is the effect of carboxyhaemoglobin on the O2 binding curve?

A

Shift to the left + shift down: increases O2 affinity for remaining Hb sites –> decrease in unloading of O2 in tissues
1. venous PO2 will be lower than anemia (2 kPa) –> headache, convulsion, come and death

206
Q

What is peripheral cyanosis and what are its causes?

A

Reduced blood flow to a region resulting in hypoxic tissue causing a bluish grey tinge in the extremities;
Causes: cardiovascular shock, low T, reduced CO, poor arterial supply

207
Q

What is central cyanosis and what are its causes?

A

Arterial hypoxemia (reduced O2 content) –> buccal, mucosa and lips turn blue
O2 saturation is less than 85% if Hb concentration is normal
Causes: COPD or right to left heart shunts

208
Q

How is CO2 carried in blood?

A

60% as HCO3-, 30% as carbaminoHb, 10% dissolved

209
Q

What is the normal arterial blood PCO2?

A

5.3 kPa

210
Q

Which proteins participate in the formation of carbamino compounds?

A

lysine and arginine side chains

211
Q

What is the Haldane effect?

A

At any given PCO2 the quantity of CO2 carried is greater in venous than in oxygenate blood due to:

  1. CO2 forms carbamino compounds more readily when deoxygenated
  2. Hb binds better to H+ when deoxy –> favours formation of HCO3-
212
Q

What are the normal PCO2 and CO2 content in venous and arterial blood?

A

Venous: 6.1 kPa, 520 ml/l
Arterial: 5.3 kPa, 480 ml/l

213
Q

What is the normal blood pH range?

A

7.35-7.45

214
Q

What is the Hendersson-Hasselbach equation defining the chemical equilibrium with carbonic acid?

A

pH = pKa + log ([HCO3-]/[CO2])
pKa = -log(dissociation constant of H2CO3) = 6.1
[HCO3-]/[CO2] needs to be around 20

215
Q

What is the rate of CO2 production in tissues?

A

200 ml/min

216
Q

What are the consequences of hyperventilation?

A
  1. Low PaCO2 –> cerebral vasoconstriction –> cerebral hypoxia –> dizziness and visual disturbances
  2. Alkalosis –> decreased plasma free [Ca2+] –> increased excitability of excitable cells
217
Q

What is the arterial [HCO3-]?

A

21-27 mM; for calculations 24 mM

218
Q

What is the difference between first order and zero order kinetics?

A

Zero order: rate doesn’t depend on concentration (accumulation: alcohol, phenytoin)
First order: rate depends on concentration (no accumulation)

219
Q

What is the difference between one compartment and two compartment model?

A

One compartment: decline of [A] is monophasic, instantaneous distribution (half life can be estimated anywhere on the curve)
Two compartment: distribution depends on equilibrium between central and peripheral compartments, biphasic decline

220
Q

How do you determine elimination rate constant (k) and initial concentration ([A0]) from a time vs ln[A] graph?

A 
k = slope
[A0] = y intercept
221
Q

How are half life and elimination rate constant (k) related?

A

half life = ln2/k

222
Q

How is volume of distribution calculated?

A

Vd = total amount of drug dosed/plasma concentration at t0

High volume of distribution (>3.5L) –> drug distributed in extracellular tissue

223
Q

What is the difference between Phase I and II metabolism?

A

Phase I: you make compound more water soluble (usually in the liver; i.e. oxidation)
Phase II: generally conjugation reactions (mostly liver)

224
Q

How do you calculate clearance?

A

Volume of blood cleared of drug per unit time; it is additive; higher = increased clearance
Cl = kVd or Cl = dose/AUC
Hepatic clearance:
Cl = hepatic extraction rationblood flow

225
Q

How do you calculate maximal oral bioavailability (F) based on the hepatic extraction ratio?

A

F = 1 - heptic extraction ratio; first pass effect

226
Q

How do you calculate oral bioavailability?

A

F = AUCoral/AUCiv

227
Q

How can PK/PD be plotted?

A

Time vs effect

228
Q

How is blood volume distributed?

A

Soluble proteins and mediators (50-60%)

Packed cell cellular volume: haematocrit (40-45%) + white blood cells and platelets

229
Q

When does haematopoiesis start and how do the sites vary in pre and post-natal periods?

A

2-2.5 weeks i.u

Yolk sac –> liver + spleen –> bone marrow

230
Q

What are the differences between totipotent, pluripotent, multipotent and unipotent/progenitor?

A

Totipotent: produces all differentiated cells
Pluripotent: either endoderm, mesoderm or ectoderm
Multipotent: multiple but restricted cell types
Unipotent/progenitor: single lineage, no potential for cell renewal

231
Q

Which two lineages does the haematopoietic pluripotent stem cell divide into?

A

Myeloid and lymphoid

232
Q

Which cells does the lymphoid lineage form?

A

NK cells, T lymphocytes, B lymphocytes and plasma cells

233
Q

Which cells does the myeloid lineage form?

A

Megakaryocyte –> platelets; erythrocytes; mast cells; myelobalast (eosinophil, neutrophil, basophil, monocyte –> macrophage)

234
Q

What are the precursor cells of RBCs?

A

Normoblast: highly condensed nucleus with Hb, a few mitochondria and ribosomes
Reticulocytes: remaining RNA and organelles are lost, 1-2 days

235
Q

What are the precursors of platelets?

A

Megakaryocytes: giant cells with single, large, irregular nucleus, cytoplasm partitioned into 2-4 microm packages by vesicles ER (platelet demarcation channels) –> ejection of platelets

236
Q

What are the characteristics of neutrophils?

A

Most abundant leukocytes (60%); polymorphonuclear; highly motile; respond rapidly to chemotactic substances –> first cell type recruited to site of inflammation; necessary during infection to clear pathogens, but lead to damage of healthy tissue in chronic inflammation

237
Q

What are the characteristics of oesinophils?

A

Cytotoxic secretory products:

  1. major basic proteins: cationic, toxic to helminthic parasites, tissue damage to host
  2. eosinophil cationic protein: bacteriocidal, promotes mast cell degranulation
  3. eosinophil derived neurotoxin: antiviral activity in respiratory infection
  4. eosinophil peroxidase: bacteriocidal
238
Q

What are the characteristics of monocytes?

A

Lifespan: months/years

horseshoe nucleus; largest leukocyte; highly phagocytotic and mobile

239
Q

What is haemostasis?

A

Arrest of blood loss from damaged vessels

240
Q

What is thrombosis?

A

Formation of occlusive thrombi leading to MI, ischaemic stroke

241
Q

What are the effects of NO and PGI2 (prostacyclin) on platelet aggregation?

A

Inhibition

242
Q

What factor do platelets produce in aggregation and what is its function?

A

TXA2 (thromboxane A2) –> vasoconstriction

243
Q

What are the effects of endothelin 1 (ET1), NO, EDHF and PGI2 on smooth muscle cells?

A

ET1: vasoconstriction

NO, EDHF, PGI2: vasodilation

244
Q

How does aggregation of platelets + vasoconstriction occur?

A

Exposure of platelets to collagen and vWF in EC matrix and later thrombin –> platelets adhere and activate –> release of mediators –> vasoconstriction + aggregation of platelets –> formation of soft platelet plug

245
Q

What are the initiation steps in the clotting pathway?

A

Extrinsic pathway: activated by TF present on TF-expressing cells (monocytes, fibroblasts) in tissues after blood, with its clotting factors, leaks out of the vessels

  1. TF + FVII –> FVIIa:TF
  2. TX + FVIIa:TF –> TXa
  3. TXa:FVa (from instrinsic pathway) + FII (prothrombin) –> FIIa (thrombin)
  4. Thrombin + fibrinogen –> fibrin and activation of platelets
    * FX and FII conversion require Ca2+ and phospholipids
246
Q

What are the amplification and propagation steps in the clotting pathway?

A

Intrinsic pathway: initiated by thrombin, involves activation of FV, FVIII, IX and X, takes place on activated platelets

  1. FXII –> FXIIa due to presence of negative charges
  2. FXIIa or IIa + FXI –> FXIa
  3. FXIa or TF:VIIa + FIX –> FIXa
  4. IIa + FVIII:vWF (in plasma) + FV (on platelets) –> FVIIIa + Va
  5. FIXa:FVIIIa + FX –> FXa
  6. FXa:FVa + FII –> FIIa
247
Q

What are tenase and prothrombinase?

A

Tenase: VIIIa:IXa –> activation of FX (tenase)
Prothrombase: Xa:Va –> activation of II (thrombin)

248
Q

What are GPIIb/IIIa receptors?

A

Integrin complex receptor on platelets for vWF and fibrinogen; aids in platelet activation

249
Q

How does fibrin deposition work?

A

Thrombin activates XIII and binds to fibrin; XIIIa leads to cross-linking of fibrin with Ca2+

250
Q

What are the differences between arterial and venous thrombi?

A

Arterial thrombosis (white clots): usually associated with atherosclerosis, form at site of vascular injury/disturbed flow, large platelet component, pro-phylaxis with anti-platelet drugs, most causes of MI and 80% of strokes;

Venous thrombosis (red clots): associated with stasis, turbulent flow of blood, vascular injury following surgery/trauma, hypercoagulability of blood, platelet component, large fibrin component, rbc component, prophylaxis with anti-coagulants, 3rd leading cause of CV death

251
Q

What are antiplatelet drugs for?

A

Limit growth of, or decrease risk of, arterial thrombosis, inhibits platelet aggregation; aspirin, P2Y12 antagonists, GPIIb-IIIa (alphaIIbbeta3) antagonists (GPIs); used for secondary prevention mostly

252
Q

What is the action of aspirin?

A

Irriversible inhibitor of COX1; low doses –> decreased TXA2 production (main product of COX1), while PGI2 synthesis is unaffected since endothelium can continuously synthesise it by COX2 –> action of PGI2 predominates (vasodilation + inhibition of platelet aggregation)

253
Q

What is the action of P2Y12 receptor antagonists?

A

P2Y12 receptor: involved in amplification of platelet activation through ADP; amplifies the action of P2Y1 activation and complete aggregation induced by other platelet agonists (ADP, collagen, thrombin, TXA2, adrenaline and 5-HT)

254
Q

What is the action of GPIIbIIIa antagonists?

A

2 drug classes: fab fragments and small molecule inhibitors, all used IV
Very potent, however major thrombocytopaenia (high rates of bleeding complications

255
Q

What are the uses of anticoagulant and fibrinolytic therapies?

A

Inhibit coagulation cascade, prophylaxis and treatment of venous thrombi; prevent propagation of blood clot but do not dissolve it (heparin, warfarin); new drugs: FX and thrombin inhibitors
Thrombolytics: used for rapid removal of the thrombus in coronary artery and cerebral artery thrombosis

256
Q

What is the major enzyme responsible for breakdown of clots and how is it produced?

A

Plasmin; tissue plasminogen activator (serine protease on endothelial cells), converts plasminogen into plasmin –> break down of fibrin clots

257
Q

What is the role of protein C?

A

protein C is activated by thrombin + thrombomodulin –> forms a complex with protein S and calcium –> degradation of Va and VIIIa

258
Q

What is the action of heparin?

A

Inhibits serine-protease factors XIIa, XIa, Xa, IXa and thrombin directly and through anti-thrombin III

259
Q

What is the action of warfarin?

A

Inhibition of Vit K dependent epoxide reductase activity (modifies FVII, IX, X and II during synthesis in liver)

260
Q

What are other types of anticoagulant drugs apart from heparin and warfarin?

A 
Factor Xa inhibitors (IV and oral)
Thrombin inhibitors (IV and oral)
261
Q

What is TFPI?

A

Tissue factor pathway inhibitor, from endothelial and other cells, inactivates and forms a complex with Xa –> inactivation of TF:VIIa complex

262
Q

What is the relation between APC and tPA?

A

APC inhibits plasminogen activator inhibitor (PAI) –> stimulates activation of tPA

263
Q

What are examples of fibrinolytics?

A

Streptokinase and alteplase (both activate plasminogen)

264
Q

How do you calculate AUC?

A

AUC = dose/(Vd*k)

FBS2 (3 decks)

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