2018A

2018 (1st sitting)

Question 1

Question

Describe the carriage of oxygen in the blood, including total oxygen delivery per minute

Example answer

Oxygen is transported in the blood in two main forms:

Dissolved oxygen
Combined with haemoglobin (oxyhaemoglobin)

Dissolved oxygen

Amount of oxygen dissolved in blood is proportional to Henrys Law
There is 0.03ml oxygen per 1L blood for each mmHg of PO2 at 37 degrees
Thus for PO2 of 100 there is 3 ml dissolved oxygen per 1L blood

Oxyhaemoglobin

98% of oxygen in the blood is carried by haemoglobin
Haemoglobin reversibly binds O2 and transports it around the body
One haem group binds 1 oxygen molecule. Each Hb molecule binds four O2 molecules
Oxygen capacity of Hb (1g of Hb carries 1.34ml Oxygen)
Binding of O2 to Hb
- Hb exists in tense (unbound) and relaxed (bound states)
- As Hb binds oxygen, it exhibits positive cooperativity (additional binding is easier), as the R state Hb has increased oxygen affinity. Explains sigmoidal shape of oxy-dissociation curve
Oxygen bound to Hb does not contribute to PO2 of blood - maintaining diffusion gradient

Oxygen content of blood (CaO2)

<math display="inline">CaO_2 = (1.34 \; \times \; [Hb] \; \times \; SaO_2) \; + \; (0.03 \times PO_2)</math>
Where [Hb] is the Hb concentration, 1.34 is the oxygen carrying capacity of Hb (Huffners constant), SaO2 is the percentage of Hb saturated with oxyge, 0.03 is the dissolved oxygen content of blood, and PO2 is the partial pressure of oxygen in blood

Oxygen delivery (DO2)

Oxygen delivery (DO2) is a function of the cardiac output and oxygen content of blood (CaO2)
- <math display="inline">DO2 \; = \; CO \; \times CaO_2</math>
- <math display="inline"> DO2 \; = \; CO \; \times (1.34 \; \times \; Hb \; \times \; SaO_2) \; + \; (0.03 \times PO_2)</math>
Assuming CO of 5L/min, 100% sats, 150g/L Hb, PO2 of 100mmHg = 1L/min

Examiner comments

32% of candidates passed this question.

Better answers divided oxygen carriage into that bound to haemoglobin and that carried in the dissolved form. A reasonable amount of detail on the haemoglobin structure and its binding of oxygen was expected, including an explanation of co-operative binding and the oxygen carrying capacity of haemoglobin. Better answers mentioned Henryâ€™s law in the description of dissolved oxygen, along with an estimation of the amount of oxygen that is normally in the dissolved form.
It was expected that answers include the equation for oxygen delivery, a brief description of the components of that equation and the normal value, which a large number of candidates omitted.

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Question 2

Question

Compare and contrast the pharmacology of adrenaline and milrinone

Example answer

Name	Adrenaline	Milrinone	Comments
Class	Naturally occurring catecholamine	Phosphodiesterase inhibitor	Different classes
Indications	Haemodynamic support, anaphylaxis, bronchoconstriction/airway obstruction	Haemodynamic support for acute heart failure	Adrenaline has more/other uses
Pharmaceutics	Clear solution, light sensitive (brown glass), 1:1000 or 1:10,000	Yellow solution, 10mg/ml ampoules,
Routes of administration	IV, IM, INH, ETT, Topical, subcut	IV only in AUS	Milrinone only IV in Aus.
Pharmacodynamics
MOA	Non-selective adrenergic receptor agonist. At low doses B effects dominate, at high doses alpha dominate. Adrenaline > a-1 receptor > increased IP3 (2nd messenger) > increased Ca Adrenaline > B1,B2,B3 receptors > increased cAMP (second messenger)	PDE III inhibition > decreased cAMP breakdown > increased Ca	Different MOA - can be used synergistically
Effects	CVS: vasoconstriction (high doses), vasodilation (low doses), increased inotropy + chronotropy RESP: bronchodilation, increased minute ventilation METABOLIC: hyperglycaemia (glycogenolysis, lipolysis, gluconeogenesis) CNS: increased MAC GIT: decreased intestinal tone/secretions	CVS: increased inotropy, lusitropy, minimal chronotropy, vasodilation	Milrinone is cardiovascularly selective.
Side effects	Extravasation > tissue necrosis, pHTN due to increased PVR, hyperglycaemia, tachyarrhythmias,	May precipitate an arrhythmia, hypotension (vasodilator)	Milrinone is a vasodilator and may need adjunct vasopressor
Pharmacokinetics
Onset/Offset	Immediate / immediate	5-10 minutes / 3 hours	Adrenaline has faster onset/offset
Absorption	Zero oral bioavailability due to GIT inactivation. variable/erratic ETT absorption.	Readily absorbed orally (tablets not available in AUS)	Milrinone readily PO absorbaable
Distribution	Poor lipid solubility, doesn't cross BBB, crosses placenta	Small VOD = 0.4L/kg, protein binding 80%
Metabolism	Metabolised by MAO (mitochondria) and COMT (liver, blood, kidney) to VMA and metadrenaline	Minimal hepatic metabolism (10%)
Elimination	T 1/2: ~2 mins (due to rapid metabolism) Metabolites (above) are excreted in the urine	Renal excretion (unchanged 80%). T1/2 = 3 hours	Milrinone requires dose adjustment in renal impairment + has longer half life
Special points		Dose adjust in renal failure

Examiner comments

45% of candidates passed this question.

This question was best answered using a table. Better answers included: the mechanisms of action, the pharmacokinetics and pharmacodynamics, indications for use and adverse effects. To complete the answer, the two drugs should have been compared and contrasted. There are many areas which could be contrasted e.g. different indications, different mechanisms of action, different half-lives and duration of action, different metabolism and different pharmacodynamic effects, in particular the effects on the cardiovascular system and the pulmonary circulation. Similarities should also have been highlighted.

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Question 3

Question

Define dead space and its components (30% of marks). Explain how these may be measured (35% of marks) and describe the physiological impact of increased dead space (35% of marks).

Example answer

Dead space

The fraction of the tidal volume that does not participate in gas exchange
Made up of
- Apparatus dead space
  - Related to artificial breathing circuits/equipment (e.g. NIV)
- Physiological dead space (sum of alveolar and anatomical dead space)
  - Alveolar dead space
    - Volume of gas in poorly perfused lung units (West Zone 1)
  - Anatomical deadspace
    - Volume of gas in conducting airways
    - Approx 2ml/kg

Measurement of dead space

Physiological deadspace
- Calculated using the modified version (Enghoff) of the Bohr Equation
  - <math display="inline">\frac {V_D}{V_T} = \frac {P_aCO_2 - P_ECO_2}{P_aCO_2}</math>
Anatomical deadspace
- Can be calculated using Fowlers method
  - Subject exhales to residual volume. Pure oxygen is inhaled to total lung capacity. Subject breathes out through a nitrogen sensor. A nitrogen concentration vs volume can be generated
  - The midpoint of phase 2 = anatomical dead space
Alveolar dead space
- Equals the difference between physiological and anatomical dead space

Impact of increased dead space

Increasing dead space has the same effects on gas exchange as decreased tidal volumes
- Reduced CO₂ clearance
- Decreased oxygenation (due to increased CO2)
This results in decreased efficiency of ventilation
- For any given minute volume, CO2 clearance is reduced
- Leads to increased minute ventilation > increased work of breathing

Examiner comments

59% of candidates passed this question.

Some candidates failed to provide a correct definition of dead space. An outline of anatomical, alveolar and physiological dead space was expected. The Bohr equation was commonly incorrect, and many did not comment on how to measure the components of the Bohr equation. Fowlerâ€™s method was generally well described though some plotted the axes incorrectly.
The impact of increased dead space was not often well explained. Very few people stated the major impact of increased dead space is reduced minute ventilation and how this would affect CO2.

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Question 4

Question

Describe the renal handling of sodium

Example answer

Renal handling of sodium

Sodium is freely filtered in the glomerulus
PCT:
- ~60-70% reabsorbed
- Driven predominately by Na/K ATPase pump on the basolateral membrane which creates an electrochemical gradient for Na to flow down into.
dLOH
- Nil reabsorbed (impermeable)
aLOH
- ~25% reabsorbed
- Driven by the Na-K-2Cl co-transporter
DCT
- ~5% Na reabsorbed
- Driven by the Na-Cl co-transporter
Collecting duct
- <5% Na reabsorbed
- Driven by ENaC channels

Regulation

Tubuloglomerular feedback (release of renin in response to reduced Na/flow sensed at the JGA)
Aldosterone
- Increases ENaC and Na/K ATPase activity in the DCT and collecting ducts
Angiotensin II
- Increases Na/K ATPase activity on basolateral membrane - creates electrochemical gradient
- Increases Na-H reabsorption on luminal membrane in PCT
ANP
- Inhibits ENaC (in collecting ducts)
Pharmacological agents

Examiner comments

46% of candidates passed this question.

A description of filtration and reabsorption, including amounts was required. Better answers described sodium handling in a logical sequence as it progressed through the nephron including the percentages reabsorbed in each segment. In addition to the amounts reabsorbed, the mechanisms of transport across the tubular luminal and basolateral membranes into interstitial space should have been described.

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Question 5

Question

Compare and contrast the pharmacokinetics and pharmacodynamics of IV fentanyl and IV remifentanil (60% of marks). Discuss the concept of context sensitive half-time using these drugs as examples (40% of marks).

Example answer

Name	Fentanyl	Remifentanyl
Class	Opioid Synthetic phenylpiperidine derivative	Opioid Synthetic phenylpiperidine derivative
Indications	Analgesia	Analgesia
Pharmaceutics	Colourless solution (50ug/ml)	Crystalline white powder for reconstitution
pKa	8.4	7.3
Routes of administration	SC, IM, IV, epidural, intrathecal, transdermal	IV, intranasal
Pharmacodynamics
MOA	Mu-opioid receptor agonist > hyperpolarisation	Mu-opioid receptor agonist > hyperpolarisation
Effects	Analgesia	Analgesia
Side effects	CVS: bradycardia Resp: respiratory depression, blunted cough reflex GIT: decreased GI motility, nausea/vomiting CNS: Dysphoria, confusion,	CVS: bradycardia + hypotension Resp: respiratory depression GIT: Decreased GI motility MSK muscle rigidity at high doses
Pharmacokinetics
Onset/Offset	Rapid onset (2-5 mins) Rapid offset (30mins)	Rapid onset (1 mins) Rapid offset (5-10mins)
Absorption	PO bioavailability (33%). Mucosal absorption is poor	PO Bioavailability (0%). Mucosal absorption is rapid
Distribution	VOD high = 6L / kg Highly protein bound (90%) Good lipid solubility	VOD low = 0.1L/kg Highly protein bound (70%) Very lipid solubility
Metabolism	Hepatic metabolism > demethylation > inactive metabolites	Ester hydrolysis by plasma and tissue esterases > inactive metabolites
Elimination	T 1/2 = 4 hours, prolonged with infusions. Excreted in urine	T 1/2 5 mins. No CSHT Excreted in urine

Context sensitive half time (CSHT)

CSHT is the time required for 50% decrease in central compartment drug concentration after an infusion of the drug is ceased (context refers to the duration of infusion)
Drugs with high VOD and minimal metabolism (e.g. fentanyl) will have different CSHT depending on the duration of infusion
- Short infusion = short CSHT. Long infusion = long CSHT
Drugs with small VOD and extensive metabolism (e.g. remifentanil) has a CSHT which is independent of duration of infusion

Examiner comments

66% of candidates passed this question.

Well-constructed answers were presented in a table to compare pharmacokinetics and pharmacodynamics with a separate paragraph to discuss the concept of context sensitive half-time. Important pharmacokinetic points included: the differences in lipid solubility, ionised fractions and onset, and differences in metabolism. Marks were awarded for a definition of context-sensitive half-time. A discussion of these two drugsâ€™ context-sensitive half-times should have included the differences in re-distribution into other compartments and rates of elimination.

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Question 6

Question

Define a buffer (25% of marks). Describe how acid and base shifts in the blood are buffered (75% of marks).

Example answer

Buffers

A solution consisting of a weak acid and its conjugate base
Main function is to resist change to pH, with the addition of stronger acids/bases, through reversible binding of H+ ions
Effectiveness depends on the buffer pKa, the pH of the solution, the amount of buffer present, whether the system is open or closed
All buffers participate in equilibrium with each other in defence of pH (Isohydric principle)

MAIN BUFFER SYSTEMS

Bicarbonate-carbonic acid system

pKa of 6.1
Consists of weak acid (H₂CO₃) and base (HCO₃ salt)
Via reaction: <math display="inline"> CO_2 \; + H_2O \; \leftrightarrow \; H_2CO_3 \; \leftrightarrow \; HCO_3^- \; + H^+</math>
Increased acid > increased CO₂ (excreted via lungs)
Increased base > increased HCO₃ (excreted via kidneys)
OPEN system - hence most important - responsible for 80% of the ECF buffering

Protein buffering system (including Hb)

Includes haemoglobin (150g/L) and plasma proteins (70g/L)
Proteins buffer by binding H+ to imidazole side chains of their histidine residues
Hb is quantitatively 6 times more important than plasma proteins, as the concentration is double and there are three times as many histidine residues in Hb compared to plasma proteins
Hb has pKa of 6.8. Weak acid (HHb) and weak base (KHb)
Mechanism: H+ binds to the histidine residues on imidazole side chains, the HCO₃ diffuses down concentration gradient into ECF

Phosphate buffering system

Overall pKa 6.8
Tribasic (HPO₄, H₂PO₄, H₃PO₄) though only the H₂PO₄ has a physiological pKa to be useful
Overall contribution is minimal to the blood due to the low concentration of phosphate. However more important in the urine where the concentration is higher
closed system

Examiner comments

45% of candidates passed this question.

Few candidates defined a buffer making it difficult to award 25% of the marks for this question. The three main buffers in blood should have been described: bicarbonate system, haemoglobin and proteins. The pKa, the buffering mechanism and the capacity of the system should have been described. The Henderson Hasselbach equation was sometimes incorrect. Marks were only awarded for buffers in blood and unfortunately some candidates described non-blood buffers.

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Question 7

Question

Outline the blood supply to the gastrointestinal system (arteries and veins).

Example answer

Arterial supply

The aorta (and its branches) supplies the entire arterial supply to the GIT
The oesophagus is supplied by various arterial branches
- Cervical portion- inferior thyroid artery
- thoracic portion - bronchial arteries
- Abdominal portion - left gastric, inferior phrenic arteries
The abdominal aorta then has three main branches which supply the remainder of the GIT
- Celiac trunk
  - Arises from abdominal aorta immediately below aortic hiatus at T12/L1
  - Divides into left gastric artery, splenic artery, common hepatic artery
    - Left gastric a. (supplies stomach)
    - Splenic a. (supplies spleen, pancreas)
    - Common hepatic, divides into
      - Hepatic a. proper (supplies liver)
      - Gastroduodenal (supplies pancreas, duodenum, stomach)
      - Right gastric (supplies stomach)
- Superior mesenteric artery (SMA)
  - Arises from abdominal aorta immediately interior to coeliac trunk (L1)
  - Multiple branches (15-20) which joint in an arcade
  - supplies the midgut structures (from duodenum to 2/3 transverse colon)
- Inferior mesenteric artery (IMA)
  - Arises from abdominal aorta ~L3
  - Multiple branches (including Left colic, sigmoid, superior rectal arteries), join in arcade
  - Supplies the hindgut (distal 1/3 transverse colon - rectum)

Venous drainage

For the most part, the venous drainage of the GIT is via veins which accompany the arterial system
They return via the portal vein
- Portal vein
  - Combination SMV and splenic vein
  - Receives drainage from forgut structures
- Splenic vein
  - Travels along with the splenic artery + drains corresponding regions (foregut)
  - Combines with SMV to form portal vein
- Superior mesenteric vein (SMV)
  - Travels along with the SMA + drains corresponding regions (midgut)
  - Combines with splenic vein to form portal vein
- Inferior mesenteric vein (IMV)
  - Travels along with the IMA + drains corresponding regions (hindgut)
  - Drains into the splenic vein

Examiner comments

7% of candidates passed this question.

An outline of the blood supply from the oesophagus down to the anus was expected. Very few candidates knew the branches of the main 3 arteries and which portion of the gastrointestinal system they supplied. Concepts related to control of blood flow and autoregulation of blood flow were not asked and therefore marks were not awarded for this information.

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Question 8

Question

Outline the principle of co-oximetry (40% of marks), describe what a co-oximeter is able to measure (30% of marks), and compare its limitations to those of a pulse oximeter (30% of marks).

Example answer

CO-oximetry

A laboratory device that uses spectrophotometry to measure relative blood concentrations of Hb species
Principle
- Blood sample is heparinised, heated to 37 degrees, haemolysed by vibations
- Multiple wavelengths of light are then passed through the sample and the absorption spectra is assessed, using principles of Beer-Lambert law
- There is no need for pulsatile flow
There is becoming available pulse co-oximetry which is similar to pulse-oximeters though can detect some of the other Hb species (e.g. COHb)

Measured indices

SaO2 %
Total [Hb]
Met Hb %
Sulpha Hb %
CO Hb %
Most co-oximetry machines can also obtain all the regular blood gas tensions/values

Interpretation

	High pulse oximetry	Low pulse oximetry
High Co-oximetry	Reflects normal SpO2	Reflects normal SpO2 Differences possibly due to: 1) Poor tissue perfusion + shock 2) Dyes (e.g. methylene blue) 3) Tricuspid regurgitation 4) Poor probe contact 5) Contamination (ambient light)
Low Co-oximetry	Reflects low SpO2 Differences possibly due to: 1) Carboxyhaemaglobinaemia 2) Methaemaglobinaemia 3) Radiofrequency interference	Reflects low SpO2

Co-oximeter vs Pulse-oximeter

Advantages of co-oximetry
- More accurate sats (i.e. low reading = low sats) as accounts for other Hb species
- Not confused by ambient light, poor tissue perfusion, dyes etc
- Does not require pulsatile flow
Disadvantages of co-oximetry
- More invasive (requires blood sample) - though pulse co-oximetry becoming available
- Heavy machinery, requiring calibration, less accessible
- Not continuous measurements

Examiner comments

32% of candidates passed this question.

Most candidates confused co-oximetry with other methods of measuring oxygenation of blood. Whilst there were a number of excellent descriptions of pulse oximetry, these attracted no marks for the first two sections. Structuring the answer based on the three parts asked, would have improved answers ensuring all aspects of the question were addressed.

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Question 9

Question

Describe the functions of the placenta (80% of marks). Outline the determinants of placental blood flow (20% of marks).

Example answer

FUNCTIONS OF PLACENTA

Nutrient/gas exchange

The foetus relies on maternal transfer of gasses, nutrients and wastes
Nutrients/wastes
- Active transport e.g Amino acids, calcium, some vitamins/minerals
- Facilitated diffusion e.g. glucose (GLUT1 and GLUT3)
- Passive diffusion e.g. Na, Cl, urea, creatinine
Gasses
- Oxygen
  - Passive diffusion
  - Facilitated by higher oxygen carrying capacity and affinity of foetal Hb as well as the Bohr/Double bohr effects
- Carbon dioxide
  - Passive diffusion
  - Facilitated by the Haldane and double Haldane effects

Immunological function

Foetus is genetically distinct with a non functioning immune system
Trophoblast cells
- Lose MHC molecules and become coated in mucoprotein > less immunogenic
Chorionic cells
- Prevent maternal T cells and most immunoglobulins (except IgG) from entering > less immunogenic
- Barrier to some bacteria/viruses and allows IgG across > some immune protection
Yolk sac
- a-fetoprotein and progesterone are immunosuppressive > less immunogenic

Endocrine function

Syncytiotrophoblast of placenta produces
- B-HCG - prolongs corpus luteum (prevents early miscarriage)
- Oestrogen - increases uteroplacental blood flow, stimulates uterine growth
- Progesterone - uterine relaxation, development of lactation glands
- hPL - maternal lipolysis, breath growth/development

PLACENTAL BLOOD FLOW

Flow

Blood flow to the uterus in a non pregnant woman is normally around 200mls/min (~4% of CO)
In a pregnant woman at term this increases to up to 750mls/min (~15% of CO)
Majority of this > placenta, with some supplying the hypertrophied uterus.

Determinants of flow

No autoregulation of uteroplacental blood flow
Most important factor governing flow is therefore perfusion pressure
- Increased uteroplacental perfusion pressure > increase flow
Uterine perfusion pressure is therefore effected by
- Maternal MAP
  - Effected by positioning (e.g. aortocaval compression), cardiac output, systemic vascular resistance
- Intrauterine pressure
  - Effected by contractions > increased intrauterine pressure > decreased flow
- Uterine vascular ressistance
  - Modestly effected by exogenous vasopressors, catecholamines
Compensates for the lack of autoregulation by increasing oxygen extraction

Examiner comments

32% of candidates passed this question.

Many candidates provided a broad overview of functions of the placenta but lacked detail. Placental blood flow has maternal and foetal components, though most only considered the maternal circulation to the placenta and didn't mention the foetal vessels. Many were not specific as to what blood vessels were described.
Many stated that uterine blood flow is not autoregulated, however went on to describe myogenic and neuro-humoral mechanisms of autoregulation.

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Question 10

Question

Outline the advantages (15% of marks) and disadvantages (85% of marks) of the clinical use of suxamethonium.

Example answer

Suxamethonium

Depolarising muscle relaxant
Used to facilitate endotracheal intubation during anaesthesia (i.e. RSI)
MOA: Binds to the nACh receptor on motor end plate > depolarisation. Cannot be hydrolysed by Acetylcholinesterase in NMJ > sustained depolarisation > muscle relaxation

Advantages

Cheaper than other NMB agents
Pre-mixed
Can be IV or IM
Rapid onset (<1 min)
Rapid offset (< 10 mins)
Safe in pregnancy/neonates
Not end-organ dependant for metabolism (plasma cholinesterase)

Disadvantages

Needs to be stored at 4 degrees
Numerous side effects
- Major: anaphylaxis, suxamethonium apnoea, malignant hyperthermia

Minor: hyperkalaemia, myalgia, fasiculations, bradycardia/arrhythmia
Pressure related: increased IOP, ICP, intragastric pressure.

Numerous contraindications
- Hyperkalaemic patients and those at risk (renal failure, sepsis, burns)
- Burns patients
- Personal/family history of malignant hyperthermia or plasma cholinesterase deficiency
- Muscular dystrophies, myasthenia gravis
- Penetration eye injury
Issues with repeat dosing
- Repetitive dosing may lead to phase 2 (depolarising) block > requiring reversal

Examiner comments

46% of candidates passed this question.

This commonly used drug should be very well-known. The question asked for an outline, hence long explanations of various aspects of pharmacology (e.g. pseudocholinesterase deficiency) were unnecessary.
Headings should have included: advantages (e.g. rapid onset, rapid offset, short acting, IV or IM administration, not end organ dependent for metabolism, premixed, safe in pregnancy and neonates). The disadvantages section should have included the following headings: pharmaceutical, adverse drug reactions (including several potentially fatal ones), numerous contraindications, unpleasant side-effects and potential problems with repeat dosing.

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Question 11

Question

Describe the regulation of the coronary circulation

Example answer

Coronary blood flow

Normal resting coronary artery blood flow (CBF) is ~250mls/min (5% CO)
RCA: blood flow is constant, pulsatile and higher flow rate during systole
LCA: blood flow is intermittent, pulsatile, and higher flow rate during diastole
Oxygen extraction is high (70%) and near maximal - increased CBF is needed for increased O2 demand.

Regulation of flow

Autoregulation
- CBF is autoregulated over a wide range of BPs (perfusion pressure 50-120mmhg)
- Metabolic autoregulation
  - Anaerobic metabolism > increased vasoactive substances (lactate, adenosine, CO2, NO) > vasodilation > increased flow
  - Predominant means of autoregulation
- Myogenic autoregulation
  - Increased transmural pressure > vasoconstriction > flow reduction
  - Modest means of autoregulation
Direct autonomic control
- Weak effect
- a1 activation > vasodilation; B/muscarinic activation > vasoconstriction
Indirect autonomic control
- Increase / decrease HR to alter time in diastole/systole which will lead to increased/decreased flow
- i.e. Increased PSNS activity > decreased HR > increased diastolic time > increased CBF
External (e.g drugs)
- Nitrates (dilate)
- BBlockers (reduce HR > reduced O2 use and increased diastole time)
- CCB (coronary vasodilation)

Examiner comments

46% of candidates passed this question.

Some answers suffered from listing things rather than describing things as the question required.
Better answers included a description of metabolic, physical and neuro-humoral factors and the relative importance of each.
Many described detailed anatomy which was not necessary.

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Question 12

Question

Briefly describe the cardiac events that occur during ventricular diastole.

Example answer

Cardiac cycle

Can be broken into two phases: systole and diastole
Diastole is the phase corresponding to ventricular relaxation
Diastole can be broken into 4 stages (below; using LV as example)

Isovolumetric relaxation

Aortic valve closes (producing 2nd heart sound) ending systole, beginning diastole
LV begin to relax without any change in volume > decreasing LV pressure
There is ongoing LA filling leading to increased LA pressure and the V wave.
Corresponds with the peak of the T wave

Early diastolic (rapid ventricular) filling

When LV pressure < LA pressure the mitral valve opens
This leads to increased LV volume and reduced LA pressure (the y descent on CVP waveform)
With continued ventricular relaxation there is ongoing decrease in LV pressure
This corresponds to the 3rd heart sound and isoelectric baseline on ECG
There remains no further aortic flow
Coronary blood flow is highest

Late diastolic (reduced ventricular or diastasis) filling

Ongoing slow ventricular filling leading to gradual rise in atrial, ventricular and venous pressures as well as ventricular volume
Corresponds to isoelectric baseline on ECG just prior to P wave

Atrial systole

Begins just after the start of the P wave on ECG and finish before Q wave
Leads to atrial contraction which increases atrial pressure, and leads to further ejection of blood into the ventricles (increasing LV volume and pressure).
Atrial contraction produces the a wave on the CVP trace
Fourth heart sound heard here: caused by oscillation of blood into ventricles following atrial systole

Examiner comments

29% of candidates passed this question.

Many answers lacked structure and contained insufficient information. Better answers defined diastole and described the mechanical events in the 4 phases of diastole. A common error was the ECG events in diastole. The electrical events and coronary blood flow should have been mentioned.

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Question 13

Question

Explain the difference between viscosity and density (10% of marks). Describe the effects of changes in viscosity and density on the flow of gases and liquids (90% of marks).

Example answer

Viscosity (n)

Liquids/gas internal resistance to flow

Density (p)

Mass of a substance per unit volume

Flow (Q)

The volume of liquid/gas moved per unit time
Can be laminar, turbulent or transitional - determined by Reynolds number

Reynolds number

<math display="inline">Re \; = \; \frac {2 \; r \; v \; p} {n}</math>
Where r = radius, v=velocity, p=density, n=viscosity
If Reynolds number is
- Re <2000 = laminar flow
- Re 2000-4000 = transitional flow
- Re >4000 flow is predominately turbulent
Increased density (p) = increased Reynolds number = more likely to be turbulent flow
Increased viscosity (n) = decreased Re = more likely to be laminar flow
Density is a more important determinant of Re

Laminar flow

Smooth flow of gas in layers that do not mix
Flow is proportional to driving pressure, linear relationship
Flow (Q) rate can be calculated using the Hagen-Poiseuille equation
<math display="inline">Q = \frac {\pi r^4 \Delta P}{8nl}</math>
<math display="inline">Resistance (R) = \frac {8nl} {\pi r^4}</math>
Therefore viscosity (n), not density, affects the laminar pressure-flow relationship
- Increased viscosity = increased resistance = decreased flow

Turbulent flow

Eddies and swirls of gas that mix layers of gas
Flow is proportional to the square root of driving pressure, non linear relationship
Resistance increases in proportion to flow rate, but cannot be described using the Hagen-Poiseuille equation but instead by the Fanning Equation
Density (p), not viscosity, affects the turbulent pressure-flow relationship

Examiner comments

46% of candidates passed this question.

Whilst most candidates defined density correctly, there was a lot of uncertainty regarding viscosity. Most candidates recognised that flow may be laminar, turbulent or transitional. Most accurately recounted Reynolds number and applied this correctly. Additionally, the Poiseuille equation was correctly stated by most candidates and correctly related to laminar flow. Few candidates recalled the equation describing turbulent flow.

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Question 14

Question

Classify anticholinesterase drugs according to chemical interaction with an example of each (30% of marks). Outline the pharmacodynamic effects of anticholinesterase drugs and their clinical indications (70% of marks).

Example answer

Anticholinesterase drugs

Bind to and inhibit the action of Acetylcholinesterase (AChE)
AChE is an enzyme found in synaptic clefts which hydrolyses acetylcholine (ACh) into choline and acetate, terminating synaptic transmission

Anticholinesterase drugs classification (according to method of inhibition)

Reversible antagonists (via electrostatic binding)
- E.g. edrophonium
Reversible antagonist (via covalent bonding, susceptible to hydrolysis)
- e.g. neostigmine, physostigmine
Irreversible antagonist (via covalent bonding, resistant to hydrolysis)
- e.g. organophosphates, insecticides, nerve gases

Pharmacodynamic effects

Anticholinesterase drugs inhibit AChE at both muscarinic and nicotinic ACh receptors
Nicotinic effects (nAChR) - "target"
- Reversal of non-depolarising NMBs
Muscarinic effects (mAChR) - "off target"
- CVS: bradycardia, hypotension
- RESP: bronchoconstriction/spasm
- CNS: miosis, cholinergic syndrome (confusion, agitation, nausea)
- GIT: hypersalivation, increased GIT motility, N/V
- GUT: urination/incontinence
- OTHER: diaphoresis, lacrimation

Clinical indications

Reversal of non-depolarising neuromuscular blockers
- Increased synaptic ACh competes with non-depolarising NMBs for nAChR > reversal of NMB (e.g. neostigmine, plus atropine/glycopyrrolate to offset AEs)
Diagnosis + treatment of myasthenia gravis
- Increased synaptic ACh > competes with myasthenia autoantibodies for nACHR > increased muscle strength (e.g. pyridostigmine)
Treatment of neurodegenerative disorders
- Increased synaptic ACh > increased cholinergic transmission (e.g. donepezil)
Treatment of glaucoma
- Increased ACh > mAChR > miosis > decreased IOP (e.g. physostigmine)
Treatment of anticholinergic syndrome
- features: delirium, tachycardia, dilated pupils, agitation, seizures
- Drugs: antiparkinsons, atropine, anti histamines, antispasmodics
- Management: physostigmine > increase ACh

Examiner comments

32% of candidates passed this question.

Many candidates who scored poorly confused anticholinesterase drugs with anticholinergic drugs. Some described pharmacokinetics when it was not asked. Similarly, treatment of organophosphate poisoning and/or cholinergic crisis was not asked for in the question.

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Question 15

Question

Describe the physiological regulation of intracranial pressure

Example answer

Intracranial pressure (ICP)

ICP = The pressure within the intracranial space, relative to atmospheric pressure
Normal ICP is < 15 mmHg
Governed by the Monro-Kellie doctrine
There is rhythmic variation in ICP due to variations in respiration and blood pressure

Monro-Kellie doctrine

The skull is a rigid container of fixed volume
The skull contents include: brain (~1400ml), CSF (~150ml), blood (~150ml)
Therefore any increase in volume of one substance must be met by a decrease in volume of another, or else there will be rise in the ICP

Physiological regulation of ICP

Brain tissue
- No capacity to alter volume under physiologically normal circumstances
CSF
- CSF can be displaced from the cranium into the spinal subarachnoid space (as the spinal meninges have better compliance)
- With increased ICP there is also increased driving pressure for CSF reabsorption
Blood
- Compression of the dural venous sinuses can displace venous blood from the cranium

Pressure volume relationship

Hyperbolic relationship - indicating that there is limited capacity to buffer increased volume, before large increases in ICP

image-20211012142839178

Examiner comments

45% of candidates passed this question.

A definition and a normal value were expected. A description of the Monro-Kellie doctrine was expected. Better answers divided into the various components of the cranium with the answer focussing on cerebral blood volume and CSF volume as the brain tissue as no capacity to change its volume.

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Question 16

Question

Compare and contrast the pharmacology of furosemide (frusemide) and acetazolamide

Example answer

Name	Frusemide	Acetazolamide	Notes
Class	Loop diuretic	Carbonic anhydrase inhibitor	Different class
Indications	Oedema/fluid overload, renal insufficiency, hypertension	Metabolic alkalosis, glaucoma, altitude sickness	Different indications
Pharmaceutics	Tablet, clear colourless solution (light sensitive),	White scored tablets (250mg), colourless solution	-
Routes of administration	IV, PO,	PO, IV	Both available IV and PO
Dose	Varies (~40mg daily commonly used for well patients, can be sig. increased)	125mg-1g, up to 4 hourly	-
pKA	3.6 (highly ionised; poorly lipid soluble)	pKa 7.2	Acetazolamide more lipid solu
Pharmacodynamics
MOA	Binds to NK2Cl transporter in the thick ascending limb LOH, leads to decreased Na,K, Cl reabsorption > decreased medullary tonicity + Inc Na/Cl delivery to distal tubules > decreased water reabsorption > diuresis	Inhibits carbonic anhydrase in PCT > decreased reabsorption of filtered HCO3	Different MOA
Effects	Renal: diuresis CVS: hypovolaemia, arteriolar vasodilation + decreased preload (=mechanism for improvement of dyspnoea before diuretic effect in APO) Renal: increase in RBF	CNS: decreased IOP by decrease aqueous humour RENAL: diuresis, decreased HCO3 reabsorption (metabolic acidosis),	Both lead to diuresis/hypovolaemia. Acetazolamide has extra-renal effects (e.g. IOP effects)
Side effects	CVS: hypovolaemia, hypotension Renal/metabolic: Metabolic alkalosis, LOW Na, K, Mg, Cl, Ca, increased Cr Ototoxicity, tinnitus, deafness	CNS: paraesthesia, fatigue, drowsiness RENAL: hypoNa, HypoK, HyperCl GIT: Nz/Vz/Dz	Both lead to electrolyte disturbances (hypoNa and HypoK). Frusemide > metabolic alkalosis, Acetazolamide > metabolic acidosis
Pharmacokinetics
Onset	5 mins (IV), 30-60 mins (PO), Effect lasts 6 hours.	Onset 1-2hrs	Frusemide has faster onset
Absorption	Bioavailability varies person-person (40-80%)	PO bioavailability 60%	Similar
Distribution	Vd = 0.1L/Kg, 95% protein bound (albumin)	95% protein bound, VOD 0.3L/kg	Both have small VOD and are highly protein bound
Metabolism	< 50% metabolised renally into active metabolite	Nil metabolism	Acetazolamide not metabolised
Elimination	Renally cleared (predominately unchanged). T1/2 ~90 mins.	Renal clearance, T 1/2 = 6hrs	Acetazolamide has longer T1/2
Special points	Deafness can occur with rapid administration in large doses

Examiner comments

30% of candidates passed this question.

The use of a table assisted with both clarity and the ability to compare the two drugs. Writing separate essays about each makes it difficult to score well. It was expected that candidates would follow a standard pharmacology format and discuss pharmaceutics, pharmacokinetics, pharmacodynamics and adverse drug reactions. Both of these drugs are â€˜Level Aâ€™ in the syllabus and a suitable level of detail was expected.
It was expected candidates would discuss in detail the mechanism of action, electrolyte and acid-base effects. Pharmacokinetic values were poorly answered. Qualitative terms such as â€˜moderate, good and someâ€™ are vague and should be avoided. Only correct numerical values (or ranges) attracted full marks.

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Question 17

Question

Define the osmolality and tonicity of an intravenous fluid (20% of marks). Compare and contrast the pharmacology of intravenous Normal Saline 0.9% and 5% Dextrose (80% of marks).

Example answer

Osmolality

The measure of solute concentration per unit mass of solvent.
Measured in osmoles / kg solvent

Tonicity

The measure of the osmotic pressure gradient between two solutions separated by a semi permeable membrane
Only influenced by the solutes which cannot cross the semi-permeable membrane
Can be hypotonic, isotonic, hypertonic

Normal saline vs 5% dextrose

Name	0.9% normal saline (IV)	5% dextrose (IV)
Class	Crystalloid fluid	Crystalloid fluid
Pharmaceutics	Clear solution, various volume bags (e.g. 100ml, 500mls, 1L)	Clear solution, various volume bags (e.g. 1L, 500mls)
Osmolality	308 mOsm / Kg (calculated) 286 mOsm/kg (measured)	278 mOsm/kg
Tonicity	Isotonic	Hypotonic (dextrose rapidly metabolised)
Contents	9g NaCl / 1L solution	50g dextrose / 1L solution
Pharmacodynamics
MOA	Expands the ECF volume and changes biochemistry of body fluids	Expands ECF volume and changes body fluid biochemistry
Effects	Increased ECF volume	Increased ECF volume Glucose replacement
Side effects	Fluid overload, hyperchloraemic metabolic acidosis, electrolyte imbalances	Fluid overload, cerebral oedema, hyperglycaemia, vein irritation, electrolyte imbalances (e.g. HypoNa)
Pharmacokinetics
Onset	Immediate (IV)	Immediate (IV)
Absorption	IV bioavailability = 100%	IV bioavailability = 100%
Distribution	VOD = 0.2 L/Kg > 25% intravascular > 75% interstitial	VOD = 0.6L/Kg > 5% intravascular > 25% interstitial > 70% intracellular
Metabolism	Not metabolised	Metabolised by all body tissues (esp liver) into water and CO2
Elimination	Renal	Water eliminated renally, CO2 eliminated by lungs

Examiner comments

29% of candidates passed this question.

Most candidates gave an adequate definition of osmolality and tonicity. A single concise sentence for each attracted full marks. Some candidates drew diagrams & equations, which added few marks. Some candidates confused osmolarity (mOsm/L) and osmolality (mOsm/kg).
Tonicity was best defined as the number of â€˜effectiveâ€™ osmols (those that cannot cross the cell membrane) in a solution relative to plasma. The use of a table greatly facilitated the comparison of 0.9% saline and 5% dextrose solutions. Values for composition, osmolarity and osmolality were poorly done. Some manufacturers state calculated values and some approximate values on the bags â€“ both were accepted.
No candidate correctly pointed out the fluids respectively have 9g NaCl and 50g dextrose per litre.

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Question 18

Question

Compare and contrast non-invasive oscillometric and invasive arterial blood pressure monitoring.

Example answer

Non-invasive oscillometric vs invasive arterial BP monitoring

	Invasive arterial BP	Oscillometric (non invasive) BP
Equipment	- Arterial catheter - Incompressible tubing - Pressure transducer - Counterpressure fluid - Microprocessor	- Inflatable cuff - Cuff manometer - Release valve - Microprocessor
Method/ principles	1) Pressure wave of the arterial blood is transmitted via a fluid column to a transducer 2) Pressure changes converted to resistance changes in Wheatstone bridge transducer 3) Converted to electrical signal > transmitted to microprocessor 4) Microprocessor uses Fourier analysis to breakdown waves	1) counterpressure (cuff) applied to limb over artery (e.g. brachial) 2) cuff inflated above SBP 3) cuff deflated slowly, measuring amplitude of the pulse pressure which is transmitter to cuff 4) Maximal amplitude of PP = MAP 5) SBP and DBP are then derived
Advantages	- Gold standard BP measurement (all variables directly derived) - Can measure continuously - Can derive other variables (e.g. CO) - Can be used to generate waveform which can be used clinically	- Non invasive - Relatively cheap - Convenient and fast to obtain - Reusable
Disadvantages	- More expensive - More invasive - Takes time / less portable - All the risks associated with arterial puncture (infection, thrombosis etc) -Not re-usable	- Less accurate - Not continuous
Sources of error	- Incorrect position of transducer - Incorrect calibration - Counterpressure bag not adequately inflated - Damping and resonance	- Wrong cuff size - Movement - Arrhythmias - Faint pulse (e.g hypotension and peripheral vascular disease)

Examiner comments

52% of candidates passed this question.

There were some good answers, though invasive BP measurement was better answered than oscillometry. Many candidates provided extensive detail in one area i.e. the workings of a Wheatstone bridge, to the detriment of a balanced answer.
Few seemed to have a structure consisting of "equipment, method, sources of error, advantages, disadvantages" or similar and missed providing important information as a result. Several described auscultatory non-invasive blood pressure measurement, rather than oscillometry, which although related in principle is a different process.

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Question 19

Question

Explain the mechanisms by which normal body temperature is maintained and regulated

Example answer

Overview

Temperature: the average kinetic energy of the atoms/molecules that make up a substance
Human 'core temperature' is the 'deep body' temperature of the internal organs and viscera
Humans maintain a core temperature of 37Â°C <math display="inline">\pm</math> 0.4Â°C, despite changes in ambient temperature
- Rectal, bladder, oesophageal, central vascular temperatures are often used as approximations.
Peripheral temperatures are variable and generally less than the core temperature
Significant hypothermia (e.g. <35Â°C) or hyperthermia (e.g. >41Â°C) can lead to multi-organ dysfunction
Humans have multiple thermoregulatory mechanisms to resist change in core body temperature
In general, heat is lost by 4 mechanism: conduction, convection, evaporation, radiation
In general, heat is gained by 5 mechanisms: conduction, convection, evaporation, radiation, metabolism

Thermoregulatory system & regulation

Sensor
- Peripheral: Skin thermoreceptors (cold= bulbs of Krause; warm=bulbs of Ruffini)
  - Travels via spinothalamic tract to hypothalamus
- Central: Hypothalamic thermoreceptors
Integrator/controller
- Hypothalamus
  - Functions as the thermostat
  - Stimulation of anterior hypothalmus leads to heat loss
  - Stimulation of the posterior hypothalamus leads to heat conservation/generation
Effector/Response
- Response to cold
  - Shivering -> involuntary muscle contractions that generate heat (ATP hydrolysis)
  - Peripheral vasoconstriction (ANS) --> decreased cutaneous blood flow --> decreased heat transfer from ambient air
  - Increase metabolic rate, thyroid hormone secretion, Non shivering thermogenesis (paeds) -> increased heat generation
  - Behavioural changes (seek warmth)
  - Piloerection (unimportant in humans)
- Response to heat
  - Peripheral vasodilation (ANS) --> increased cutaneous blood flow > increased heat loss
  - Sweating --> evaporative heat loss
  - Behavioural changes (seek cool)

Examiner comments

52% of candidates passed this question.

The best answers were systematic, using a sensor, integrator, effector approach, while also mentioning physiological variations i.e. diurnal, with ovulatory cycle etc.
Few candidates raised the concept of central and peripheral compartments. The differentiation of the concepts of set point, interthreshold range and thermoneutral zone was often confused.

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Question 20

Question

Outline the structure (20% of marks) and function (80% of marks) of the hypothalamus.

Example answer

Overview

Small (4g) almond shaped structure
Posterior: mammillary bodies. Anterior: anterior commissure. Superior: thalamus. Inferior: pituitary
Can be broken up into four functional regions, with discrete nuclei with various functions

Structure and function

Region	Nuclei	Function
Anterior hypothalamus	- Supraoptic nuclei (ADH, oxytocin) - Paraventricular nuclei (TRH, CRH)	- PSNS activity (increased) - Thermoregulation (leads to heat loss) - Water balance (ADH production / release) - Sleep/wake cycle (promotes sleep)
Medial hypothalamus	- Ventromedial nuclei - Dorsomedial nuclei	- Sexual function (release of GnRH) - Energy balance (BGL) - Satiety centre (inhibits appetite)
Lateral hypothalamus	- Tuberal nuclei - Forebrain bundle	- Behaviour/emotions (inc. punishment/reward) - Regulation of body water (thirst centre) - Regulation of hunger (increased)
Posterior hypothalamus	- Mammillary nuclei	- SNS activity (increased HR, BP, constriction) - Vasomotor control - Thermoregulation (heat gain) - Sleep wake cycle (wakefulness)

Regulation of pituitary function

Hypothalamus exerts control of pitutiary gland via two mechanisms
- Anterior lobe of pituitary
  - Controlled by secretion of hypothalamic hormones along the portal vein
    - TRH > TSH release
    - CRH > ACTH release
    - GHRH > GH release
    - GnRH > TSH/FSH release
    - PRH > prolactin
- Posterior lobe pituitary
  - Controlled by direct neural connections from the anterior hypothalamus > pituitary
  - Pituitary hormones (ADH, oxytocin)

Examiner comments

21% of candidates passed this question.

Most candidates understood the endocrine functions of the hypothalamus, and to some degree its interactions with the pituitary. Fewer candidates mentioned the importance of the hypothalamus as an integrator for the autonomic nervous system, or its roles in arousal/emotions.
Many candidates had only a vague idea of the structure of the hypothalamus, while the best candidates were able to relate function to structure quite accurately.

2018 (1st sitting)

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