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
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
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
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.
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.
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)
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.
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
The drug is evenly distributed (often not the case)
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.)
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.
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.
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.
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.
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
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)
Alter antibiotic target site
Alteration to Peptidoglycan binding site protein, reducing affinity of drug.
E.g. Vancomycin and VRE (e.g. E. faecium)
Modification / inactivation of drug
E.g. ESBL and penicillin's/cephalosporins whereby b-lactamases hydrolyse B-lactam rings
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.
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
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
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
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.
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
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.
Answers should have included the various types of shock and provided clear examples. Cardiovascular responses including sensor, integrator, effector mechanisms were necessary to pass.
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).
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).
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.
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).
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.
- 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.
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.
