2019A

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Question 1

Question

Describe the pharmacology of lignocaine.


Example answer

Name Lidocaine (lignocaine)
Class Amide anaesthetic / Class 1b antiarrhythmic
Indications Local/regional/epidural anaesthesia, ventricular dysrhythmias
Pharmaceutics Clear colourless solution (1%, 2%, 4%). Can come with/without adrenaline. Also available as cream/spray
Routes of administration SC, IV, epidural, inhaled
Dose Regional Use: Toxic dose 3mg/kg (without adrenaline), 7mg/kg (with adrenaline)

IV use: 1mg/kg initially, then ~1-2mg/kg/hr

pKA 7.9, 25% unionised at normal body fluid pH
Pharmacodynamics
MOA Class 1b anti-arrhythmic: blocks Na channels, raising threshold potential + reducing slope of Phase 0 of action potential, shortened AP

Local anaesthetic: binds to, and blocks, internal surface of Na channels

Effects Analgesic, anaesthetic, anti-arrhythmic
Side effects CNS: headache, dizziness, confusion, paraesthesia, reduced LOC, seizures

CVS: hypotension, bradycardia, AV Block, arrhythmia
CC/CNS ratio = 7 (lower number = more cardiotoxic)

Pharmacokinetics
Onset Rapid onset (1-5 minutes)
Absorption IV > Epidural > subcut. Oral bioavailability 35%
Distribution 70% protein bound, Vd 0.9L/kg. Crosses BBB
Metabolism Hepatic, some active metabolites
Elimination Metabolites excreted in urine. Half life ~90mins. Increased with adrenaline (SC). Reduced in cardiac/hepatic failure.
Special points


Examiner comments

16% of candidates passed this question.

Comprehensive answers included uses (including antiarrhythmic action and a role in analgesia), physical properties and preparations, pharmacodynamics and pharmacokinetics. Its mode of action should also have been described. Many candidates focussed on toxicity and its management but provided little information on pharmacodynamics and pharmacokinetics, commonly omitting factors which affect its systemic absorption. Other common omissions were the dose required for its local anaesthetic effect and for its antiarrhythmic effect


Online resources for this question


Similar questions

  • Question 17, 2014 (1st sitting)

  • Question 2, 2021 (2nd sitting)


Question 2

Question

Outline the components required to measure blood pressure from an intra-arterial catheter (75% of marks). What information (other than blood pressure) may be gained from an arterial line trace (25% of marks)?


Example answer

Components

  • Intra-arterial catheter
    • narrow (generally 18-22G) and relatively short - minimises resonance
    • Provides conduit to transmit blood pressure wave to circuit
  • Fluid filled tubing
    • Permits hydraulic coupling of mechanical signical
    • Non compressible fluid filled (usually saline) tubing minimises damping
  • Counterpressure bag with flush system
    • pressure of~300mmHg - counteracts arterial pressure
    • Fluid provides slow continuous infusion to maintain catheter patency (prevent clots etc)
    • Can be used for diagnostic/trouble shooting purposes with 'fast flush test'
  • An electrical transducer
    • Usually a Wheatstone bridge peizoresistive transducer
    • Movement of the diaphragm caused by arterial pressure changes leads to stretching/compression of the strain gauges and is converted into an electrical signal
    • Placed at phlebostatic axis and requires calibration
  • Microprocessor + amplifier
    • Processor uses Fourier analysis to break down the waveform into component sine waves which are reconstructed with 8-10 harmonic sine waves
    • Amplifies signal
  • Cabling
    • To transmit the information/electrical signals
  • Monitor
    • To visualise the information (including pressures and waveform)
  • 3 way tap
    • Allows sampling of arterial blood for diagnostic purposes
    • Allows 'zeroing' to atmosphere for calibration


Information gained

  • Heart rate
  • Heart rhythm - regular or irregular
  • Blood pressures - Systolic pressure, diastolic pressure, mean arterial pressures, pulse pressures
  • Pulse pressure variation
  • Issues with system - Dampened trace may indicate kinks, bubbles, clots in the circuit
  • Cardiac output, stroke volume, stroke volume variation by pulse contour analysis (e.g. FloTrac)
  • Waveform may indicate underlying pathology with modest accuracy (e.g. collapsing wave in AS)


Examiner comments

44% of candidates passed this question.

Most of the marks were allocated to the components of the measuring system (as detailed in the question), hence a level of detail was required. An explanation of how the various components work was required; e.g. hydraulic coupling and transducers. Some candidates forgot to include heart rate as a piece of information derived from the trace.


Online resources for this question


Similar questions

  • Previous questions on damping/resonance - nil on arterial line setup.



Question 3

Question

Compare and contrast fresh frozen plasma and prothrombin complex concentrate


Example answer

Name FFP Prothrombinex
Description Human plasma including all coagulation factors Human plasma derivative containing a concentrate of specific clotting factors
Preparation 1) Separation of whole blood or apheresis

2) Frozen and stored
3) Rethawed in water bath prior to use

1) Separation of whole blood or apheresis

2) Separation of clotting factors II, IX and X via ion exchange chromatography
3) Freeze dried powder

Indications Coagulopathy

Plasma exchange
ACE-I angioedema, suxamethonium apnoea

Warfarin reversal

Correction of coagulopathy from factor II, IX or X deficiency

Pharmaceutics 250-300ml bags, labelled with donor blood types Glass vial with powdered concentrate for reconstitution with water. Generally 500U per vial

Contains small amount of heparin

Storage Stored for 12 months Stored for 6 months
Routes of administration IV IV
Dose 2-4 units (varies) 25-50 u/kg
Contraindications ABO incompatibility DIC, HITS (contains heparin), liver failure
Contents/factors All clotting factors (except fibrinogen) Contains factors II, IX, X (500 units each)
Adverse effects Blood product, with all the risks associated with this (fluid overload, infection, allergic responses) Allergic or anaphylactic reactions

Thrombosis in predisposed individuals

Pros Contains all necessary clotting factors

Less expensive than PTX

Does not need group/crossmatch (therefore available for immediate use)

Smaller fluid volume

Cons Requires ABO grouping

Requires time for thawing etc
More fluid, more side effects

Factor 7 absent

More expensive than FFP


Examiner comments

10% of candidates passed this question.

Very few answers included details on prothrombin complex concentrate which meant it was difficult to score well. Useful headings included preparation and administration, dose, indications and adverse effects. Not many candidates knew the dose of FFP, and few were able to describe the preparation/production of the product. Few candidates knew the factors available from either product. Commonly missed was the need for ABO typing for FFP and that Prothrombin complex concentrate did not require this.


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  • ? None



Question 4

Question

Outline the functional anatomy of the kidney (40% of marks). Outline the regulation of renal blood flow (60% of marks)


Example answer

Gross anatomy of kidney

  • Gross anatomy
    • Paired retroperitoneal organ
    • Sits at ~ T12-L3 (right lower than left)
  • Structure
    • Outer fibrous capsule > Outer 'cortex' > Inner 'medulla' > renal pelvis
  • Blood supply
    • Arterial: renal arteries from abdominal aorta
    • Venous: renal veins > IVC
  • Innervation
    • SNS (T9-13)


Functional anatomy

  • The nephron is the basic functional unit of kidney (~1-2 million nephrons per kidney)
    • 85% of nephrons are predominately located in cortex (cortical nephrons)
    • 15% are juxtamedullary and extend deep into the medulla.
  • Nephron structure
    • Renal corpuscle (filtration): with glomerulus + bowman's capsule
    • Juxtaglomerular apparatus (adjustments to GFR): contains macula densa, JG cells, mesangial cells
    • Tubular system (reabsorption/regulation): PCT > LOH > DCT
    • Collecting duct system
  • Vascular
    • Afferent arteriole: blood supply to individual nephron
    • Efferent arteriole: carries blood away from individual nephron


Renal blood flow regulation

  • Normal RBF = ~20% of CO (~1L / min), predominately distributed to cortex > medulla
  • Kidneys are able to autoregulate (maintain constant blood flow) across a wide range of MAP (~70-170mmhg)
  • Myogenic regulation
    • Intrinsic constriction of afferent arterioles in response to increased transmural pressure of vessel wall (e.g. increased BP)
  • Tubuloglomerular feedback
    • Regulated by macula densa
    • Increased perfusion pressure > Increased Na/Cl sensed by macula densa > adenosine released > constriction > decreased GFR. Vice versa (except NO is released with decreased Na/Cl delivery to vasodilate and increased GFR)
  • Neuronal control
    • SNS activation > afferent and efferent arteriole constriction > decreased flow
  • Hormonal control
    • Renin-angiotensin system: Renin released (SNS stimulation, hypotension, decreased Na at JGA) > increased AG1 > increased AG2 > constriction of arterioles > decreased RBF/GFR


Examiner comments

71% of candidates passed this question.

It was expected that answers include sections on the blood supply, the nephron (including the difference between the cortical and juxta-medullary nephrons) and innervation. A number of candidates failed to quantify renal blood flow and to define autoregulation. The concept that it’s the flow that’s regulated was not described by some. Tubuloglomerular feedback was generally described correctly but a reasonable number had the blood flow increasing when an increased sodium was sensed at the macula densa.


Online resources for this question


Similar questions

  • Renal blood flow and autoregulation
    • Question 18, 2007 (1st sitting)
    • Question 12, 2008 (2nd sitting)
    • Question 11, 2012 (1st sitting)
    • Question 3, 2015 (2nd sitting)
  • Functional anatomy of kidneys
    • Question 21, 2011 (2nd sitting)
  • Functional anatomy + autoregulation of blood flow
    • Question 18, 2017 (1st sitting)



Question 5

Question

Define volume of distribution (15% of marks). Outline the factors affecting volume of distribution (60% of marks) and explain how it may be measured (25% of marks).


Example answer

Volume of distribution

  • The theoretical volume in which an amount of drug would distribute to produce an observed plasma concentration
  • Note: Does not correspond to any real volume. Can often exceed total body water


Measurement

  • Assumes that

    1. The drug is evenly distributed (often not the case)

    2. Metabolism and elimination have not taken place (often not the case)

  • Requires drug dose to be given, then plasma samples to be taken

  • Semilogarithmic plasma concentration vs time curve plotted.

  • In a single compartment model, VOD can then be calculated as VOD = dose given / plasma concentration at time 0 (which is back extrapolated on the curve from 1st time point.)

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Factors affecting volume of distribution

  • Patient factors
    • Age: decreasing water content with age = decreased Vd (water soluble drugs)
    • TBW: decreases with age = decreased Vd (water soluble drugs)
    • Fat %: increased body fat = increased Vd of lipophilic drugs
    • Gender: women generally have lower Vd (water soluble drugs) due to lower TBW but higher Vd for fat soluble drugs
  • Drug factors
    • Molecular size: decreased size = increased Vd
    • Lipid solubility: increased lipophilicity = increased Vd
    • pKa: basic drug in low pKa = increased Vd
    • Protein binding: increased protein binding = decreased Vd
    • Charge: ionised molecules > may be traped in central compartment > decreased Vd
  • Logistical factors
    • Timing of measurement
    • Modelling used (e.g. single compartment)
  • Pathological factors
    • Renal failure/hepatic failure: may lead to low protein = decreased Vd
    • Oedema, ascites - reservoir for water soluble drugs


Examiner comments

51% of candidates passed this question.

The first two parts of the question were reasonably done. Most candidates had well-structured answers which included drug factors and patient factors. In addition to listing the factors it was expected candidates state how these factors affect volume of distribution. Explaining how volume of distribution is determined was not so well done.


Online resources for this question


Similar questions

  • Question 12, 2015 (second sitting)



Question 6

Question

Outline the physiology of the adrenal gland (70% of marks). Describe the actions of aldosterone (30% of marks).


Example answer

Adrenal gland

  • Paired organs, immediately superior to kidneys
  • Broken up into an outer adrenal cortex (80%) and an inner adrenal medulla (20%)


Adrenal cortex

  • Three zones of cells
  • Zona glomerulosa
    • Outermost zone of cortex
    • Synthesises mineralocorticoids (e.g. aldosterone)
    • Important for regulation of electrolytes (Na, K) and water balance
    • Regulated by ACTH from anterior pituitary, angiotensin II and plasma potassium levels
  • Zone fasiculata
    • Secretes glucocorticoids (e.g. cortisol ~95% of activity)
    • Widely important, particularly for metabolism and cardiovascular function (HR, BP etc)
    • Regulated by ACTH from the anterior pituitary gland
  • Zona reticularis
    • Innermost zone of cortex
    • Secretes androgen precursors (e.g. DHEA) which get converted into testosterone and oestrogen
    • Regulated by ACTH and androgen stimulating hormones


Adrenal medulla

  • Innermost portion of the adrenal gland
  • Responsible for producing catecholamines (adrenaline, noradrenaline)
  • Chromaffin cells (modified neuroendocrine cells) are responsible for storing/synthesising the catecholamines
  • Regulated by SNS activity from T5-T11 (thus stress, hypoglycaemia, etc can activate)


Aldosterone

  • Primary mineralocorticoid hormone from adrenal gland (90% of activity)

  • Actions of aldosterone

    • Increases reabsorption of Na in the DCT and CD (principle cells)

    • Increases secretion of potassium in the DCT and CD (principle cells)

    • Increased Na reabsorption in sweat glands, salivary glands and GIT

    • Increases ECF volume (by increased H2O reabsorption by osmosis with the Na)

    • Increased H+ excretion in DCT (leads to Cl reabsorption and metabolic alkalosis)


Examiner comments

43% of candidates passed this question.

Lack of breadth and detail were in many of the answers. Physiology of the adrenal gland includes an outline of the adrenal medulla, the types of chromaffin cells, hormones secreted and how secretion is stimulated. The three zones of the adrenal cortex should have been outlined including substances secreted, their function and again how their secretion is stimulated. The actions of aldosterone should have been described; a comment on sodium and water excretion was insufficient to attain many marks for this section. The extra-renal actions of aldosterone were missing from most answers.


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  • None ?



Question 7

Question

Compare and contrast the pharmacokinetics and pharmacodynamics of midazolam and dexmedetomidine.


Example answer

Name Midazolam Dexmedetomidine Notes
Class Benzodiazepine (sedative) Central alpha agonist (sedative) Diff. classes
Indications Anaesthesia, sedation, treatment of seizures, anxiolysis Short term sedation and anxiolysis Dexmed = short term and no anticonvulsant / amnesic properties
Pharmaceutics IV: clear solution, pH 3.5. Diluted in water. Clear colourless isotonic solution. Or white powder for dilution
Routes of administration IV, IM, S/C, intranasal, buccal, PO IV only in AUS Midaz has more routes available
Dose Dose depends on many pt. factors. 1-5mg premedication. 2.5-10mg seizures. Infusions. Infusion (though loading boluses can be given)
pKa 6.5 7.1
Pharmacodynamics
MOA Midazolam (BZD) binds to GABAA receptors (ionotropic ligand gated channel) in the CNS. Cl enters > hyperpolarisation. Selective central a2 agonism (predom. at the locus coeruleus and spinal cord) Different receptors
Effects CNS: sedation, amnesia, anticonvulsant effects, decreased cerebral O2 demand CNS: Sedation, anxiolysis No amnesia with dexmed
Side effects CVS: bradycardia, hypotension

CNS: confusion, restlessness
RESP: respiratory depression/ apnoea

CVS: hypotension, bradycardia

Other: hyperthermia, confusion, dry mouth

Bradycardia worse with dexmed. No Resp depression with dexmed.
Pharmacokinetics
Onset peak effect 2-3 minutes (IV) ~30 mins (without bolus) Midaz = quicker onset
Absorption ~40% oral bioavailability

Absorbed well, but sig. 1st pass metabolism

IV only in Aus. Low PO bioavailability Midaz has greater PO bioavailability
Distribution 95% protein bound, very lipid soluble

Vd = 1L / kg

95% protein bound, very lipid soluble

Vd = 1.3L/kg

Similar
Metabolism Hepatic metabolism by hydroxylation

Active (1-a hydroxymidazolam) and inactive metabolites

Biotransformation (direct glucuronidation and CYP450 metabolism) > inactive metabolites Midas has active metabolites
Elimination Renal excretion

T 1/2 = 4 hours

Renal excretion (5% stool)

t 1/2 = 2 hours

Similar
Special points Flumazenil - antagonist (reversal agent) Atipamezole = antagonist (reversal agent)


Examiner comments

27% of candidates passed this question.

Most candidates used the effective tabular format presenting pharmacokinetics and pharmacodynamics of each drug side by side. Many answers demonstrated a lack of correct detail with respect to the pharmacokinetics and pharmacodynamics of these two level 1 drugs. Many included pharmaceutics which attracted no marks as it was not asked.


Online resources for this question


Similar questions

  • Midazolam
    • Question 9, 2019 (2nd sitting)
    • Question 4, 2018 (2nd sitting)
    • Question 24, 2016 (1st sitting)
    • Question 2, 2008 (2nd sitting)
  • Dexmed
    • Question 22, 2015 (1st sitting)
    • Question 5, 2012 (1st sitting)
    • Question 2, 2008 (2nd sitting)



Question 8

Question

Compare and contrast the measurement (40% of marks) and interpretation (60% of marks) of both central venous and mixed venous oxygen saturations.


Example answer

Central venous oxygen saturations (ScvO2)

  • The oxygen saturation of haemoglobin at the cavo-atrial junction
  • Normally measured using a CVC
  • ScvO2 is normally ~70% (slightly lower than SmvO2 in well patients due to higher oxygen extraction from upper body)
  • ScvO2 is used as a surrogate for SmvO2 as it is more accessible for most ICU patients as need a CVC not PAC


Mixed venous oxygen saturation (SmvO2)

  • The oxygen saturation of haemoglobin when measured in the pulmonary artery (after venous mixing in the right ventricle)
  • Measured using a pulmonary artery catheter
  • SmvO2 is normally ~75%
  • SmvO2 provides better idea of whole body venous O2 sats (blood from SVC, IVC and coronary sinus)
  • Can be used to estimate the cardiac output via the modified fick equation
    • CO = oxygen consumption / (Oxygen content arterial blood - oxygen content mixed venous blood)


Measurement

  • Both can be measured using the same methods
    • Intermittent sampling
      • ABG: derivation of the SvO2 value from the PO2, pH and pCO2, using the oxygen-haemoglobin dissociation curve.
      • Co-oximetry: measures absorption of near-IR light by haemoglobin species, and the use of the Beer-Lambert law to calculate the concentrations of oxyhaemoglobin and deoxyhaemoglobin
    • Continuous monitoring
      • Using a CVC or PAC with with fibre optic reflectance spectrophotometer
      • Near IR light reflectance strength used to determine ratio of Oxy and deoxy Hb


Interpretation of ScvO2 / SmvO2

  • Increased saturation
    • Anaesthesia
    • Septic shock
    • Cyanide toxicity
    • High output cardiac failure
    • Hypothermia
    • Severe liver disease
  • Decreased saturation
    • Cardiogenic shock
    • Septic shock
    • Hyperthermia
  • Importantly, not sensitive to regional hypoxia/dysoxia


Evidence

  • No evidence to support targeting ScvO2 or SmvO2 saturations at present


Examiner comments

8% of candidates passed this question.

Many candidates did not appreciate that ScvO2 refers to SVC / RA junction venous oximetry and not femoral or peripheral venous oximetry. Methods of measurement such as co-oximetry and reflectance spectrophotometry needed to be explained. Marks were awarded for the normal values. Discussion of the relationship between ScvO2 and SmvO2 and changes during shock attracted marks. Better answers quoted the modified Fick equation and related this to cardiac output and factors affecting oxygen consumption versus delivery.


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Question 9

Question

Classify antibiotics with respect to their mechanism of action (50% of marks). Outline the mechanisms of antimicrobial resistance (50% of marks). Give specific examples of each.


Example answer

Classification of antibiotics

  • Inhibitors of cell wall synthesis
    • Beta-lactams: e.g. flucloxacillin
    • Cephalosporins: e.g. ceftriaxone
    • Carbapenems: e.g. meropenem
    • Monobactams: eg. aztreonam
    • Glycopeptides e.g. vancomycin
  • Inhibitors of cytoplasmic membrane function
    • Polymyxins: e.g. colistin
    • Lipopetides e.g daptomycin
  • Inhibitors of nucleic acid synthesis
    • Quinolones e.g ciprofloxacin
    • Rifamycins e.g. rifampicin
    • Nitroimidazoles e.g. metronidazole
  • Folate metabolism inhibitors
    • e.g. trimethoprim
  • Inhibitor of protein synthesis
    • Aminoglycosides: e.g. gentamycin
    • Tetracyclines: doxycycline
    • Lincosamides: e.g clindamycin
    • Macrolides: e.g. erythromycin


Antimicrobial resistance

  • Occurs when the maximal level of drug tolerated in insufficient to inhibit growth
  • Broadly occurs via genetic alteration or changes to protein expression


Mechanisms of resistance

  1. Prevent access to drug target
    • Decrease permeability
      • E.g. pseudomonas aeruginosa resistance to carbapenems due to reduction in porins
    • Active efflux of drug
      • Efflux pumps > extrude antibiotics (eg. fluoroquinolone resistance with E.coli)
  2. Alter antibiotic target site
    • Alteration to Peptidoglycan binding site protein, reducing affinity of drug.
    • E.g. Vancomycin and VRE (e.g. E. faecium)
  3. Modification / inactivation of drug
    • E.g. ESBL and penicillin's/cephalosporins whereby b-lactamases hydrolyse B-lactam rings
  4. Modification of metabolic pathways
    • Metabolic pathways bypass site of antibiotic action
    • E.g. Bactrim resistance (synthesise their own folic acid)


Examiner comments

70% of candidates passed this question.

This question was well answered. Marks were awarded for correct pairing of mechanism of action and resistance with examples of drug class. Few mentioned the mechanisms by which resistance is present; acquired or generated.


Online resources for this question


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  • Question 5, 2020 (1st sitting)



Question 10

Question

Outline the sequence of haemostatic events after injury to a blood vessel wall (50% of marks). Discuss the role of naturally occurring anticoagulants in preventing clot formation in-vivo (50% of marks).


Example answer

  1. Vascular constriction
    • Occurs instantly, lasts a few minutes
    • Due to
      • Local myogenic spasm
      • Nervous reflexes
      • Release of local vasoconstrictors (e.g. Thromboxane A2)
    • Limits the amount of haemorrhage and creates environment suitable for clot formation


  1. Primary haemostasis (platelet plug formation)

    • Platelet adhesion

      • Exposed vWF in endothelium binds to glycoprotein receptor complex on platelets

      • Platelet GP1a binds to subendothelial collagen fibres by vWF bridge

    • Platelet activation

      • Activated following exposure to tissue factor, vWF and collagen

      • Results in them

        • Changing shape (large, more irregular, pseudopod formation) > assists with clot formation

        • Release molecules (Thromboxane A2, ADP, serotonin) > vasoconstricts + activates platelets

    • Platelet aggregation

      • Activated platelets bind fibringoen, vWF and fibronectin forming a soft platelet plug

  2. Secondary haemostasis (clot formation)

    • Two main models: classical (in vitro) model and modern cell based (in vivo) model

    • Cell based model

      • Initiation

        • Vessel damage exposes plasma to tissue factor

        • tissue factor binds to and activates factor VII

        • TF-Factor VIIa complex activates factor X

        • Factor X activates prothrombin > thrombin (small amounts)

      • amplification

        • This causes local activation of platelets (via vWF), Factor V, Factor VIII and factor XI

        • This greatly accelerates the production of thrombin around the surface of the platelets

      • Propagation

        • Begins with formation of tenase complexes on platelet surfaces (IXa-VIIIa) which greatly increases the rate of Factor X activation

        • The large amounts of Xa interacts with factor Va forming prothrombinase complex (Va-Xa) which catalyses the conversion of prothrombin to thrombin

        • Positive feedback loop


Natural anticoagulants --> prevent unnecessary coagulation

  • Antithrombin 3
    • Inactivates IIa and Xa
  • Protein C
    • Inactivates Va and VIIa
  • Protein S
    • Cofactor for upregulating protein C
  • Thrombomodulin
    • Bound to the endothelial membrane
    • Binds thrombin and activates protein C
  • Heparan
    • Activates AT-3, which in turn inactivates thrombin


Examiner comments

40% of candidates passed this question.

This question was best answered in a chronological manner. Many candidates omitted initial vasoconstriction and its mechanism. The platelet plug and formation of the clot should have then been described followed by the fate of the clot, including in-growth of fibroblasts. Strictly, fibrinolysis is a system for repairing / limiting clot propagation after the fact. Anticoagulants refer to antithrombin III, heparin, thrombomodulin and protein C and S. An explanation of the interaction of these naturally occurring anticoagulants was expected. The clotting factors that are specifically inhibited was expected as part of the discussion. The glycocalyx and vessel wall also plays a role in preventing coagulation.


Online resources for this question


Similar questions

  • Question 4 (part 2), 2009 (1st sitting)
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Question 11

Question

Describe the physiology of cerebrospinal fluid (CSF) (60% of marks). Describe the anatomy relevant to performing a lumbar puncture (40% of marks).


Example answer

CSF

  • ECF located in the ventricles and subarachnoid space
  • volume: ~2ml/kg
  • Divided evenly between the cranium and spinal column


Formation

  • Constantly produced (~24mls/hr)
  • Produced by choroid plexus (70%) and capillary endothelial cells (30%)
  • Produced by a combination of ultrafiltration (via fenestrated choroidal capillaries) and active secretion


Composition relative to plasma

  • Similar: Na, osmolality, HCO3
  • Increased: Cl, Mg, CO2
  • Decreased: pretty much everything else


Circulation

  • CSF flows from lateral ventricles > foramen of Monro > 3rd ventricle > Sylvian aqueduct > 4th ventricle > cisterna magna (via foramen megendie and luschka) > spreads between spinal/cranial subarachnoid spaces


Reabsorption

  • Reabsorption by the arachnoid villi located predominately in the dural walls of the sagittal + sigmoid sinuses (one way valves)

  • Reabsorbed at ~24mls/hr

Functions

  • Mechanical protection: low specific gravity of CSF > decreased effective weight of brain > no contact with skull base + less inertia forces
  • Buffering of ICP - CSF can be displaced / reabsorbed to offset increase in ICP
  • Stable extracellular environment for neuronal activit
  • Control of respiration: pH regulates respiration via central chemoreceptors
  • Nutrition: supply of oxygen, sugars, amino acids to supply the brain


Anatomy of LP

  • Positioning:
    • lateral decubitus or sitting position
  • Level:
    • L2-5 possible (below conus medullaris)
    • L3/4 or L4/5 are recommended (safety).
  • Surface landmarks:
    • Line between iliac crests (Tuffiers line) = L4/5
    • Line between PSISs = L3/4
    • Central positioning by spinous processes'
  • Angle of needle
    • Toward umbilicus (~15 degrees)
  • Order of tissues/structures passed through by needle
    • Skin
    • Subcut tissue
    • Supraspinous ligament
    • Interspinous ligament
    • Ligamentum flavum
    • Epidural space
    • Dura mater
    • Arachnoid mater
    • Subarachnoid space = CSF


Examiner comments

86% of candidates passed this question.

Better answers had a structure with headings such as function, formation, circulation, absorption and composition with dot point facts under each heading. The second part of the question lent itself to a diagram with labelling which scored well. Precise surface anatomy and mentioning all layers from the skin to the sub-arachnoid space scored well


Online resources for this question


Similar questions

  • Question 16, 2020 (1st sitting)

  • Question 15, 2018 (2nd sitting)

  • Question 9, 2017 (2nd sitting)

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  • Question 16, 2015 (1st sitting)

  • Question 2, 2013 (1st sitting)

  • Question 22, 2007 (1st sitting)

  • Question 6, 2008 (2nd sitting)


Question 12

Question

Compare and contrast the pharmacology of salbutamol and ipratropium bromide.


Example answer

Name Salbutamol Ipratropium bromide Notes
Class Short acting B2 agonist (synthetic sympathomimetic amine) Anticholinergic (quaternary ammonium derivative of atropine)
Indications Bronchoconstriction, hyperkalaemia, tocolytic Bronchoconstriction
Pharmaceutics Clear solution for neb, solution for IV (post dilution), powder / aerosol for inhalation, PO tablets Aerosol for inhalation, clear colourless solution for neb
Routes of administration Neb, IV, INH, PO Neb, INH Salbutamol can be given IV
Dose 2.5mg-5mg PRN (Neb)

200-400mcg PRN (INH)
0.5mch/kg.min (infusion)

Neb: 100-500mcg QID

INH: 100-500mcg BD

Salbutamol given more regularly
Pharmacodynamics
MOA B2 agonism > increased cAMP > decreased Ca > bronchial smooth muscle relaxation Competitive antagonism of muscarinic ACh receptors > bronchodilation + decreased secretions Can be used synergistically (different MOA)
Side effects CNS: anxiety, tremor

RESP: reverses HPVC
CVS: tachycardia
MET: hypoK (stimulates Na/K ATPAse), lactic acidosis

RESP: dry mouth, N, V

CNS: headache, blurred vision

Pharmacokinetics
Onset/duration Immediate, fast offset (mins) Peak effect 1-2 hours, lasts 6 hours Ipratropium has slow onset, longer duration of effect
Absorption 50% bioavailability 5% inhaled absorbed systemically Salbutamol can be given PO
Distribution VOD: ~150L/kg

10% protein bound
Can cross placenta

VOD: 4-5L/kg

Very weak protein binding

Salbutamol crosses placenta
Metabolism Metabolised in liver > inactive + active metabolites Metabolised in liver by CYP450 > inactive Salbutamol has active metabolites
Elimination Metabolites via urine + faeces
T 1/2: 4 hours
Metabolites via urine + faeces
Elimination half life 3 hours
Similar
Special points


Examiner comments

46% of candidates passed this question.

Overall candidates had a superficial knowledge of these level 1 drugs. To pass candidates needed to identify points of difference and overlap in various areas such as structure, pharmaceutics, pharmacokinetics, pharmacodynamics, mechanism of action, adverse effects and contraindications.


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Similar questions

  • None directly
  • Bronchodilators more broadly have been asked for in
    • Question 4, 2016 (2nd sitting)
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Question 13

Question

Classify circulatory shock and provide examples (40% of marks). Outline the cardiovascular responses (60% of marks).


Example answer

Shock

  • Life threatening, generalised maldistribution of blood flow resulting in failure to deliver and/or utilise oxygen, leading to tissue dysoxia.


Classifications

  • Hypovolaemic
    • Caused by intravascular volume depletion
    • Includes haemorrhage, fluid loss (e.g. dehydration) and fluid shifts (e.g. pancreatitis)
  • Cardiogenic
    • Caused by cardiac pump failure or dysfunction
    • Includes: cardiomyopathy, ACS, arrhythmia, valve failure
  • Distributive
    • Caused by significant peripheral vascular dilation leading to fall in PVR
    • Includes: sepsis, inflammation (e.g. post cardiopulmonary bypass), anaphylaxis, neurogenic (e.g. high spinal cord injury)
  • Obstructive
    • Caused by circulatory obstruction/impedance
    • Includes: tamponade, tension pneumothorax, pulmonary embolism


Cardiovascular response to circulatory shock

Stimulus Sensor Integrator Effector
Hypotension Baroreceptors Nucleus of the solitary tract (NTS) - CNX inhibition (increased HR) - SNS activation (vasoconstriction, redistribution of BV, increased CO) - RAAS activation
Decreased VO2 Aortic arch chemoreceptors NTS As above
Decreased circulatory volume Atrial myocytes - Decreased release ANP
Decreased circulatory volume Baroreceptors Hypothalamus Increased release of vasopressin
Decreased circulatory volume Renal JG cells - Increased release of renin, RAAS activation
Inadequate tissue perfusion vascular SM and endothelium - Autoregulatory vasodilation


Examiner comments

83% of candidates passed this question.

Answers should have included the various types of shock and provided clear examples. Cardiovascular responses including sensor, integrator, effector mechanisms were necessary to pass.


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  • ? None



Question 14

Question

Compare and contrast the mechanism of action, pharmacokinetics and adverse effects of digoxin and sotalol.


Example answer

Name Digoxin Sotalol Notes
Class Cardiac glycoside (antiarrhythmic) B-blocker Different class
Indications tachyarrhythmias (e.g. AF, SVT), heart failure tachyarrhythmias (e.g. AF, SVT) and ventricular arrhythmias Sotalol can be used for ventricular arrhythmias
Pharmaceutics 62.5mcg/250mcg (PO tablets), 25/250 mcg/ml (IV) 80+160mg PO tablets. IV in racemix mixture of enantiomers (through SAS). Digoxin available IV
Routes of administration IV and PO PO, IV (via SAS)
Dose Generally load with 250-500mcg, then 62.5-125mcg daily thereafter 40-160mg PO BD No loading for sotalol
pKA 7.2 9.8
Pharmacodynamics
MOA Direct cardiac: inhibits Na/K ATPase > increased Ca > positive inotropic effect + increased refractory period

Indirect cardiac: increased PSNS release of ACh at M receptors > slowed conduction at AV node/bundle

1) Non selective B-blocker (class II) > decreased chronotropy and inotropy

2) Class III activity (K channel blocker) > prolonged refractory period + repolarisation > slow AV conduction and lengthens QT

Dig = increased inotropy and short QT

Sotalol = decreased inotropy + prolonged QT

Side effects CVS: May worsen arrhythmia (lead to VF), AV block, shortened QT interval, scooped ST, TWI, bradycardia

GIT: nausea, anorexia, vomiting
CNS: dizziness, drowsiness

CVS: precipitation of tDP, bradycardia, prolonged QT int, bradycardia, hypotension

Resp: bronchospasm
CNS: dizziness, drowsiness

Dig shortens Qt, sotalol prolongs it.
Pharmacokinetics
Onset/duration 2-3 hours (PO), 10-30mins (IV), duration of action 3-4 days 2-3 hours (PO) Similar onset
Absorption 80% oral bioavailability 95% oral bioavailability Both have good OBA
Distribution Protein binding 25%

VOD 6-7L/kg

No protein binding

VOD 1-2L/kg

Dig = larger VOD and protein binding
Metabolism minimal hepatic metabolism (15%) Nil
Elimination T 1/2 48 hours

urine excretion (70% unchanged)

T 1/2 12 hours

Urine excretion (unchanged)

Dig lasts longer in system
Special points Reduce dose in renal failure, monitor with dig level. not removed by dialysis Reduce dose in renal failure

Requires SAS for IV

Both require renal adjustment


Examiner comments

19% of candidates passed this question.

Good answers listed class and the multiple mechanisms of action for both these antiarrhythmics, briefly outlining relevant downstream physiological effects and contrasting effects on inotropy. Knowledge of specific pharmacokinetic parameters of these agents was generally lacking. Clinically relevant adverse effects were frequently omitted (e.g. prolonged QT/Torsades for sotalol, hypokalaemia potentiating toxicity of digoxin).


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Similar questions

  • Digoxin
    • Question 2, 2018 (2nd sitting)
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Question 15

Question

Describe the physiology of the NMDA (N-Methyl D-aspartate) receptor (40% of marks). Outline the pharmacology of ketamine (60% of marks).


Example answer

NMDA receptor

  • Structure
    • Tetrameric, ligand gated, transmembrane receptor
  • Location
    • Abundant in the CNS (brain, spinal cord)
  • Ion permeability
    • Ca, Na, K
  • Activated by
    • Glutamate (excitatory neurotransmitter) and glycine
    • Activation leads to removal of central Mg plus (Na/Ca in, K out) > EPSP
  • Blocked by
    • Ketamine, Mg, memantidine


Name Ketamine
Class Anaesthetic (phencyclidine derivative)
Indications induction GA, conscious sedation, analgesia,
Pharmaceutics 100mg/ml. Clear colourless solution. Racemic mixture of S and R enantiomers, or S+ enantiomer alone. Water soluble.
Routes of administration IV/IM/PO/SC/PR
Dose 0-0.25mg/kg/hr (analgesia), 1-2mg/kg (GA), 0.5mg/kg (sedation)
pKa 7.5
Pharmacodynamics
MOA NMDA antagonism, weak opioid receptor agonism, weak Ca ch inhibition
Effects CNS: dissociative anaesthesia and analgesia.

CVS: increased HR/BP, decreased pulmonary and systemic vascular resistance,
Resp: bronchodilation

Side effects CNS: emergence reactions including hallucinations, unpleasant dreams. may increase ICP in non ventilated patients

CVS: may increase HR/BP, increased myocardial O2 req.
GIT: Nausea, vomiting, increased salivation
RESP: apnoea

Pharmacokinetics
Onset 30s IV, duration of effect 10-20mins
Absorption Lipid soluble > readily absorbed. But poor OBA (16%) due to 1st pass metabolism
Distribution Large (5L/kg) VOD. small protein binding (25%). Crosses placenta.
Metabolism Metabolised by CYP450 > majority inactive metabolites (norketamine active)
Elimination Elimination T1/2 = 2 hours. Kidneys (95%), faeces (5%)
Special points


Examiner comments

49% of candidates passed this question.

The NMDA receptor is a ligand gated voltage dependent ion channel located on post synaptic membranes throughout the CNS, with glutamate, an excitatory neurotransmitter, its natural ligand. A brief description of its structure, roles of glycine and magnesium, ions conducted, result of activation, role in memory and learning and agonists/antagonists was expected. Detail on structure and functions of the receptor were a common omission.
Ketamine, a phencyclidine derivative, is a non-competitive antagonist at the NMDA receptor. It is presented as a racemic mixture or as the single S(+) enantiomer (2-3 X potency). Administration routes and doses scored marks. Pharmacodynamics were generally well covered including CVS (direct and indirect effects), CNS (anaesthesia, analgesia, amnesia, delirium, effects on CBF and ICP) respiratory (bronchodilator with preservation of airway reflexes) GIT effects (salivation, N and V). Knowledge of specific pharmacokinetic parameters was less well covered, including low oral bioavailability and protein binding and active metabolite (norketamine).


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Similar questions

  • Ketamine

    • Question 4, 2018 (2nd sitting)

    • Question 22, 2015 (1st sitting)

    • Question 16, 2011 (2nd sitting)

    • Question 7, 2010 (2nd sitting)


Question 16

Question

Describe the role of carbon dioxide in the control of alveolar ventilation


Example answer

SENSORS

Peripheral chemoreceptors

  • Located in the carotid body
    • Sense a rise in PaCO2 (as well as a fall in PaO2 or pH)
    • Afferent nerve = CN IX
  • Located in the aortic body
    • Sense a rise in PaCO2 (or fall in PaO2)
    • Afferent nerve CN X


Central chemoreceptors

  • Located in the ventral medulla near the respiratory centre
  • Stimulated by a fall in pH of the CSF
  • The most important mediator of the change in pH is PaCO2 which freely diffuses across the blood-brain-barrier and dissociates into H+
  • The reduced buffering capacity (HCO3 cannot pass the BBB) make these receptors very sensitive to change in CSF pH


CENTRAL PROCESSOR

  • Respiratory centre in the medulla and pons
    • Nucleus retroambigualis --> Expiratory muscle control via UMN
    • Nucleus parambigualis --> Inspiratory muscle control via UMN
    • Nucleus ambigualis --> Pharyngeal/laryngeal muscles via CN 9/10
    • pre-Botzinger complex --> respiratory pacemaker


EFFECTORS

  • Muscles of respiration (diaphragm, intercostals, accessory muscles etc)


Ventilatory response to CO2 change

  • Linear response (increase in PaCO2 = increase in minute ventilation)
    • Left shift: metabolic acidosis, hypoxia
    • Right shift: sleep, anaesthesia, opiates
File:Https://derangedphysiology.com/main/sites/default/files/sites/default/files/CICM Primary/F Respiratory system/ventilatory response to CO2 under different conditions.jpg


Examiner comments

57% of candidates passed this question.

Better answers considered the role of CO2 in the control of alveolar ventilation in terms of sensors, central processing and effectors - with an emphasis on sensors. Features of central and peripheral chemoreceptors should have been described in detail. The PCO2/ventilation response curve is best described using a graph, with key features of the curve identified (including gradient and axes). Various factors affecting the gradient of this curve and how CO2 affects the response to hypoxic drive should be described.


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Similar questions

  • None the same, but broadly related to

    • Question 21, 2013 (1st sitting)

    • Question 1, 2015 (1st sitting)

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Question 17

Question

Explain the physiology of neuromuscular transmission


Example answer

Neuromuscular junction (NMJ)

  • Synapse between a motor neuron and a muscle cell
  • Components
    • Terminal bouton of nerve axon
    • Synaptic cleft
    • Junctional folds
    • Motor end plate
  • The neurotransmitter of the NMJ is acetylcholine (Ach) which is synthesised in the nerve axoplasm
File:C:\Users\ethan\AppData\Roaming\Typora\typora-user-images\image-20220304095424224.png


Neuromuscular transmission

  • Action potential depolarised nerve terminal
  • Voltage gated calcium channels open & calcium enters
  • Calcium influx, triggers synaptic vesicles to release Ach into the synaptic cleft via exocytosis
  • ACh diffuses across the synaptic cleft and binds to post-synaptic nicotinic receptors
    • Nicotinic ACh receptors (nAChR) are transmembrane ligand gated, ion channel linked receptors
  • Activation of nAChR leads to Na influx, which depolarises the cell (excitatory post synaptic potential)
  • Muscle contraction occurs via muscle excitation-contraction coupling
  • ACh is subsequently metabolised by acetylcholinesterase (into Acetyl CoA and choline) and the NMJ returns to its resting state
File:Https://cdn.kastatic.org/ka-perseus-images/c2792e65f78b25734f78a5f34cd296104a2e5d86.png


Examiner comments

60% of candidates passed this question.

Description of sequential events from axon conduction to detail at the neuromuscular junction was required. Well-constructed answers defined neuromuscular transmission, elucidated the structure of the neuromuscular junction (best done with a detailed diagram), described the central importance of acetylcholine, including synthesis, storage, receptors, and degradation. An ideal answer also described both pre-synaptic (e.g. voltage-gated calcium channels, exocytosis of vesicles) and post-synaptic events (acetylcholine receptors, end plate potentials, and the events that lead to excitation-contraction coupling in skeletal muscle).


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Question 18

Question

Describe the pharmacology of frusemide


Example answer

Name Furosemide
Class Loop diuretic
Indications Oedema/fluid overload, renal insufficiency, hypertension
Pharmaceutics Tablet, clear colourless solution (light sensitive),
Routes of administration IV, PO,
Dose Varies (~40mg daily commonly used for well patients, can be sig. increased)
pKA 3.6 (highly ionised; poorly lipid soluble)
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
Effects Renal: diuresis

CVS: hypovolaemia, arteriolar vasodilation + decreased preload (=mechanism for improvement of dyspnoea before diuretic effect)
Renal: increase in RBF

Side effects CVS: hypovolaemia, hypotension

Renal/metabolic: Metabolic alkalosis, LOW Na, K, Mg, Cl, Ca, increased Cr
Ototoxicity, tinnitus, deafness

Pharmacokinetics
Onset 5 mins (IV), 30-60 mins (PO), Effect lasts 6 hours.
Absorption Bioavailability varies person-person (40-80%)
Distribution Vd = 0.1L/Kg, 95% protein bound (albumin)
Metabolism < 50% metabolised renally into active metabolite
Elimination Renally cleared (predominately unchanged). T1/2 ~90 mins.
Special points Deafness can occur with rapid administration in large doses


Examiner comments

13% of candidates passed this question.

The majority of answers were well structured, some using tables and others using key headings. In general, for a commonly used drug that is listed in the syllabus as Level 1 of understanding, detailed information was lacking. In particular, mechanism of action, dose threshold and ceiling effect and pharmacokinetics lacked detail and/or accuracy.




Question 19

Question

Describe the effects of ageing on the respiratory system.


Example answer

Age relate changes Effects of change
Airway

- Increased airway reactivity
- Decreased ciliary number/activity
- Diminished airway reflexes

- Increased risk of bronchospasm

- Reduced clearance of secretions
-Increased propensity towards pharyngeal collapse

Chest wall

- Calcification of costal ligaments
-Reduced vertebral body height
-Kyphosis

- Decreased chest wall compliance

- Reduced vital capacity
- Increased RV and FRC

Respiratory muscles

- Decreased muscle mass/strength
-Decreased proportion fast-twitch fibres

- Decreased FEV1

- Fatigue develops faster

Lungs

- Senile emphysema (hyperinflation)
- Degradation of elastic fibres and supporting tissues

- Increased lung compliance

- Increased dead space
- Decreased elastic recoil
-Increased closing volume

Gas exchange

-Increased alveolar-capillary membrane thickness
-Senile emphysema

- Decline in DLCO

- Decreased surface area for gas exchange
- Increased shunt / V/W mismatch

Control of ventilation

- Decrease in efferent neural output to respiratory muscles
- Minute volume remains similar

- Reduction in response to hypoxia and hypercarbia

-Decrease in Vt --> increase in RR to maintain MV

Work of breathing Overall increased due to the net effect of the above changes


Examiner comments

5% of candidates passed this question.

Answers should have included the effects of ageing on the efficiency of gas exchange, how the expected PaO2 changes with age, and its causation. Anatomical changes should have been included as should changes in lung volumes, particularly the significance of an increased closing volume. Marks were not awarded for the effects of disease states.


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  • None :(



Question 20

Question

Describe the cardiovascular effects of positive pressure ventilation on a patient who has received a long acting muscle relaxant.


Example answer

Overview

  • Normal spontaneous ventilation generates negative intrapleural pressure
  • PPV has numerous cardiovascular implications


Effects of PPV

  • Left ventricle
    • Decreased preload
    • Decreased afterload
  • Right ventricle
    • Decreased preload
    • Increased afterload


Mechanism of PPV effects

  • Right heart
    • Increased intrathoracic pressure (ITP) is transmitted to central veins + right atrium (RA)
      • Leads to increased RA pressure > impairs venous return > decreased RV preload
      • Leads to increased pulmonary vascular resistance > increased RV afterload
    • Increased RV afterload + reduced RV preload > decreased RV stroke volume
    • Increased RV afterload leads to increased RV end diastolic pressure
      • If RVEDP is greater than LVEDP > bulging of IV septum into LV > ventricular interdependence
  • Left heart
    • Decreased preload
      • Due to reduced RV stroke volume and ventricular interdependence (explained above)
    • Decreased afterload
      • PPV > reduction in LV end systolic transmural pressure > decreased afterload (Law of LaPlace)


Net effect on cardiac output

  • If the patient has normal LV
    • Net decrease in CO
    • Decreased preload has overall greater impact compared to decreased afterload
  • If the patient has impaired LV
    • Net increase in CO
    • Decrease in afterload has overall greater impact, compared to decreased preload


Examiner comments

33% of candidates passed this question.

Structured answers separating effects of positive pressure on right and left ventricle, on preload and on afterload were expected. Overall there was a lack of depth and many candidates referred to pathological states such as the failing heart. Simply stating that positive pressure ventilation reduced right ventricular venous return and/or left ventricular afterload, without some additional explanation was not sufficient to achieve a pass level.


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Similar questions

  • None the same
  • Broadly related to physiological changes of PEEP/PPV
    • Question 17, 2009 (1st sitting)
    • Question 3, 2014 (2nd sitting)
    • Question 2, 2016, (1st sitting)