Revision as of 05:20, 13 February 2024 by 14.203.236.70(talk)(Created page with "<span id="cicm-first-part-exam---ethans-answers"></span> = CICM First Part Exam - Ethan's answers = <span id="high-yield-topics"></span> === High yield topics === <blockquote>Topics with 5 or more past questions that are identical / very similar </blockquote> <span id="physiology"></span> === Physiology === * CNS ** CSF production, regulation, flow, content, physiological role (pretty much every year) * CVS ** Myocyte vs pacemaker action potentials * Renal/fluids...")
Explain the mechanisms of transport of substances across cell membranes including appropriate examples (75%). Outline the structure of the Na+/K+-ATPase pump (25%)
Example answer
Transport across cell membranes
Mode
Mechanism
Energy expenditure
Electrochemical gradient
Example
Factors affecting
Passive (simple) diffusion
Molecule passes through cell membrane
No (passive)
With/down
CO2 and pulmonary vascular endothelium
Fick's law of diffusion
Facilitated diffusion
Molecule crosses membrane via transmembrane protein
No (passive)
With/down
Glucose with the GLUT transporter
Ficks law diffusion and number of carrier proteins
Ion channels
Membrane spanning proteins (voltage, ligand or mechanical gated) > conformational change > opening of ion channel
No (passive)
With/down
nACHR (Ach is ligand) with Na/K as ions
Concentration gradient, number of channels
Primary active transport
Molecule crosses membrane via carrier proteins
Yes (active) requires ATP
Against
Na/K ATPase pump
Availability of carrier, substrate and ATP
Secondary active transport (symport or antiport)
Molecule crosses membrane via a carrier protein, with the energy being provided for the transport of another molecule
Yes (but not directly)
Against
Na / H antiporter in principle cells of renal collecting ducts
Availability of carrier, substrate and ATP
Endocytosis
Cell membrane invaginates around a large molecule > engulfs it > contained within vesicle
Yes
Usually against
Phagocytosis
Poorly understood. ATP
Exocytosis
Vesicle (containing molecule) fuses with cell membrane > release of molecule
Yes
Usually against
Exocytosis of ACh at the pre-synaptic cleft of the NMJ
Define respiratory compliance, include its components and their normal values (25% marks). Explain the factors that affect respiratory compliance (75% of marks)
Chest wall and lung compliance are roughly equal in healthy individual (~200mls.cmH2O)
Thus normal compliance of the respiratory system is ~100mls.cmH2O
Static compliance
Compliance of the respiratory system at a given volume when there is no flow
Dynamic compliance
Compliance of the system when there is flow (respiration)
Will always be less than static compliance due to airway resistance
At a normal RR is approximately equal to static compliance
Specific compliance
The compliance of the system divided by the FRC
Allows comparisons between patients which are independent of lung volumes
Factors effecting compliance
Chest wall
Increased
Collagen disorders (e.g. Ehlers-Danlos syndrome)
Cachexia
Rib resection, open chest
Decreased
Obesity
Kyphosis / scoliosis / Pectus excavatum
Circumferential burns
Prone positioning
Lung compliance
Increased
Normal ageing
Emphysema
Upright posture
Lung volume (highest compliance at FRC)
Decreased
Loss of surfactant (E.g. ARDS, hyaline membrane disease)
Loss of functional lung volume (e.g. pneumonia, lobectomy, pneumonectomy, atelectasis)
Pulmonary venous congestion (pHTN) and interstitial oedema (APO)
Reduced long elasticity (e.g. Pulmonary fibrosis)
Positioning (e.g. supine positioning)
Examiner comments
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Question 17, 2019 (2nd sitting)
Question 14, 2017 (1st sitting)
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Question 4
Question
Describe the mechanisms of action and potential adverse effects of inhaled nitric oxide and prostacyclin
Example answer
Nitric oxide MOA (inhaled)
Pulmonary vasodilator
Diffuses into smooth muscle cell > activates guanyl cyclase > increased conversion of GTP to cGMP > decreased intracellular calcium > relaxation of smooth muscle > vasodilation
As it is inhaled it selectively vasodilates well ventilated alveoli, which leads to improved V/Q matching > decreased work of breathing and increased oxygenation
Prostacyclin MOA (inhaled)
Pulmonary vasodilator
Binds to prostacyclin receptor (IP receptor) > active GPCR > increased conversion of ATP to cAMP > decreased intracellular calcium > relaxation of smooth muscle > vasodilation
The AP propagates through gap junctions (unlike cardiac/skeletal muscle)
There is no troponin
They facilitate cross bridge formation via calmodulin instead (unlike cardiac/skeletal muscle)
Smooth muscle cells have poorly developed sarcoplasmic reticulum
Calcium influx is mainly from ECF and not from the SR (unlike cardiac/skeletal muscle)
There is DHPR/ ryanodine receptor
Calcium induced calcium release from the SR (unlike cardiac/skeletal muscle)
10x slower, lasts 30x longer
Examiner comments
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Question 13
Question
Compare and contrast the pharmacology of suxamethonium and rocuronium
Example answer
Name
Suxamethonium (succinylcholine)
Rocuronium
Class
Depolarising NMB
Aminosteroid NMB /
Non depolarising NMB
Indications
Facilitate endotracheal intubation during anaesthesia (i.e. RSI)
NMB (e.g. intubation, assist with difficult mechanical ventilation)
Pharmaceutics
Clear colourless solution (50mg/ml)
Refrigeration (4°C) - 2/52 at room temp
Precipitates with thiopentone
Clear colourless solution (10mg/ml, 5ml vial)
Refrigeration (4°C) - 3/12 at room temp
Routes of administration
IV, IM
IV
Dose (RSI)
1-2 mg/kg (IV), 2-3 mg/kg (IM)
Cant be given as infusion due to phase 2 block
0.6 - 1.2mg/kg
Can be given as an infusion but variable offset
ED95
0.3mg/kg
0.3 mg/kg
Pharmacodynamics
MOA
Binds to the nACh receptor on motor end plate > depolarisation. Cannot be hydrolysed by Acetylcholinesterase in NMJ > sustained depolarisation (i.e. Na channels remain in open-inactive state) > muscle relaxation
Inhibit the action of ACh at the NMJ by competitively binding to alpha subunit of nAChR on post junctional membrane
Decreased responsiveness to temperature change (widened interthreshold range)
Opioids also decrease sympathetic outflow > impaired vasoconstriction
If adjunct muscle relaxant used -> shivering also prevented (decreased heat generation)
Therefore the only thermoregulatory responses available to anaesthetised/paralysed patient with hypothermia are vasoconstriction and non shivering thermogenesis. Hence body temperature changes passively in proportion to the difference in heat production and heat loss
Mild hypothermia
34-36.5
Common during anaesthesia
Effects of hypothermia
METABOLIC
BMR drops 6% for every 1 degree in core temp --> Decreased VO2
Hyperglycaemia (decreased cell uptake)
CVS
Decrease inotropy and chronotropy > decreased CO
Arrhythmias (AF, VF)
QT prolongation, J wave
Resistance to DCCV
Peripheral vasoconstriction and blood redistribution
Increased risk of myocardial ischaemia
CNS
Confusion and decreasing LOC
Shivering
Seizures (increased seizure threshold)
RESP
Decreased RR
Left shift of O2 dissociation curve
GIT
Ileus
Decreased hepatic drug metabolism and clearance (slows enzymatic reactions, decreased blood flow)
HAEM
Increased HCT and blood viscosity
Coagulopathy,
Platelet dysfunction and sequestration
RENAL
Cold diuresis (decreased vasopressin synthesis)
ENDO
Decreased ACTH, TSH, vasopressin
ACID-BASE
Increased pH
Examiner comments
33% of candidates passed this question.
Sedation reduces body temperature by interfering with heat production and increasing heat loss, along with widening of hypothalamic inter-threshold range. This portion of the question was generally well answered. The question asked to "outline" the answer. Many candidates actually "described" the thermoregulation process in general but were unable to relate those with the impact of sedation. The second part of the question (physiological effect of low body temperature) was answered by most of the candidates with the structure of organ-system wise description. A few candidates scored extra marks by relating these effects with degree of hypothermia and by describing how thermogenesis responses (including shivering) can influence those effects. Some candidates restricted their answers to the effect of thermogenesis in response hypothermia and did not include the overall physiological consequences of low body temperature. Better answers displayed an understanding of core temperature regulation, inter-threshold range and the effects of sedatives on thresholds for thermogenic responses, although only a few mentioned gain and maximal response. Better answers included specific detail (mentioned bradyarrhythmia, slow AF, VF, prolonged PR/QRS / J waves rather than just stating arrhythmia) across several organ systems. Marks were not awarded for generic statements such as 'decreased liver function' without some additional detail. Inadequate depth of knowledge was main reason behind overall poor scores.
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Question 9, 2021 (1st sitting)
Question 17
Question
Write notes on:
The principles of ultrasound
Transducer properties and image resolution
The doppler effect
Example answer
Ultrasound = sound waves at higher frequencies then can be heard by humans (>20kHz)
Sound wave generation
Produced by piezoelectric effect
Electrical voltage applied to quartz (piezoelectric) crystal > vibrates > sound emitted (Converts electrical energy to sound energy)
Frequency of sound wave
Different probes emit different frequencies of sound waves:
Liner = 15-6 MHz
Curved = 8-3 MHz
Cardiac = 5-1 MHz
Effects
Higher frequency = shallower depth, better resolution
Lower frequency = better depth, less resolution
Sound wave effected by tissue and may be
Absorbed
Sound is absorbed, lost as heat
Reflected
Sound reflected off objected back to probe sensor
Reflection occurs at interfaces of tissues with different densities (impedance)
Refracted
Change in direction (bending) of sound wave
Scattered
Sound reflected from tissue but not received by probe sensor
Detection of sound
The probe spends 1% time emitting sound, 99% time listening for sound
The crystals are vibrated by returning sound waves (echos) and generates a voltage (converse piezoelectric effect)
Processing
Amplitude of the wave determines echogenicity
Time taken for echo's to return determines depth
Output mode
B mode (brightness mode)
2D crossection through tissue
Largest amplitude = brightest, smallest amplitude = darkest
M mode (motion mode)
Movement of structures over time
Resolution
Spatial resolution
Dependant on axial (parallel to beam) and lateral (perpendicular to beam) resolution
Enhances by pulse wave and focusing
Contrast resolution
Distinguish between two regions of similar echogenicitiy
Temporal resolution
Distinguish change over time
Improved by framerate
Doppler effect
The change in frequency of a wave in relation to an observer that is moving relative to the wave source.
In medical ultrasound
The change in frequency of sound waves reflected from moving tissue (e.g. erythrocytes)
Away from probe (lower frequency = blue colour)
Towards probe (higher frequency = red colour)
Examiner comments
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Question 18
Question
Describe the anatomy of the left subclavian vein
Example answer
Course
Continuation of the axillary vein (commences at the lateral border of the 1st rib)
Travels medially, first arching cephalad before heading caudally toward the sternal notch
Terminates by joining the internal jugular vein (IJV) and forming the brachiocephalic (innominate) vein behind the sternoclavicular joint
Tributaries
External jugular vein
Drains into the subclavian at the lateral border of anterior scalene muscle
Thoracic duct
Drains into either subclavian or innominate vein behind the sternoclavicular joint
Relationships
Cephalad
Skin, subcutaneous tissue, platysma
Anterior
Skin, clavicle, subclavius muscle
Posterior
Anterior scalene muscle which separates from the subclavian artery
Needle is placed in the deltopectoral groove, inferior and lateral to the middle third of the clavicle.
The needle is inserted at a shallow angle, passing under the middle third of the clavicle aiming at the sternal notch.
Examiner comments
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Question 19
Question
Describe the physiological factors that affect PaCO2
Example answer
Overview
PaCO2 is normally 40mmHg +/- 3mmHg
PaCO2 is a balance between production and elimination
CO2 production
Metabolism
CO2 is the by-product of mitochondrial respiration via TCA cycle
Increased metabolism > increased CO2 production
Metabolic rate is increased with
Exercise
Increased temp (e.g. infection)
Youth
Male sex
Pregnancy
Eating
Energy source
RQ = Ratio of Co2 produced: O2 consumed
Effected by the energy source utilised
Normally
Fats 0.7
Ketones/alcohols 0.7
Proteins 0.8
Carbohydrates 1.0
Hence carbohydrates Increase CO2 production compared to lipids/proteins (though hot chips are delicious)
CO2 elimination
Alveolar ventilaiton
CO2 is a ventilation limited gas
Increase minute ventilation (RR, TV) > increase CO2 elimination via respiration > decreased PaCO2
Physiological factors that increase RR: Pain, anxiety, pregnancy, Hypoxia
Tightly regulated
Minute ventilation is increased by increased PaCo2
MV linearly increases 2L/min for every 1mmmHg increase in PaCo2
Due to the chemoreceptor responses
Central chemoreceptors
Located: Ventral medulla
CO2 diffuses across BBB > increased H+ > decreased pH > detected by chemoreceptor > stimulate dorsal resp group > Increase MV
Peripheral chemoreceptors
Located: Carotid bodies, aortic bodies
Increased PaCo2 or decreased PaO2 > stimulate the respiratory centre > increased MV
Examiner comments
33% of candidates passed this question.
Candidates who scored well generally defined PaCO2 and proceeded to describe factors in terms of those related to production and elimination. Good answers described the key production factor as being rate of production through aerobic metabolism which is in turn influenced by substrate and BMR. Those who scored well described elimination as being dependent upon minute ventilation, which in turn is influenced by CO2 detection by chemoreceptors, specifically detailing the difference between peripheral and central. Many candidates detailed pathophysiological factors which unfortunately did not gain any marks.
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Question 20
Question
Describe the physiological control of systemic vascular resistance (SVR)
Example answer
Examiner comments
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Question 7, 2020 (1st sitting)
2021 (2nd sitting)
Question 1
Question
Describe the regulation of body water
Example answer
Overview
Water intake
Approximately 30ml/kg of water is needed to be ingested for fluid/body homeostasis
Approx 2-2.5L per day for an average person
Approximately half comes from drinking fluids, half from food and metabolic processes
Water is lost through numerous ways
Urine
Approx 1 - 1.5L / day
Obligatory loss is ~500mls to cover solute/waste clearance
Insensible losses (skin, lungs etc)
Approx 900mls / day
Faeces
Approx 100mls / day
The body tightly regulates water balance to preserve plasma osmolality and intravascular volume status, but also allow waste clearance
Preservation of blood volume takes precedence over plasma osmolality
REGULATION
Sensors
Osmoreceptors in hypothalamus detect increased (>290mosm/L) osmolality with dehydration (major)
Low pressure baroreceptors (RA, great vessels) detect reduced pressure (stretch) with dehydration
High pressure baroreceptors (carotid sinus, aortic arch) detect reduced pressure (stretch) with dehydration
Macula densa (kidneys) detect reduced GFR (Na/Cl delivery)
Integrator
Hypothalamus (anterior and lateral predominately)
Effector/effects
Release of ADH
Synthesised in hypothalamus transported to posterior pituitary for release
ADH acts on collecting ducts in the kidney in to increase aquaporins on luminal wall --> increased water reabsorption
Released in response to increase osmolality and activation of RAAS
ANP/BNP
Decreased stretch > decreased ANP/BNP secretion --> increased water reabsorption
Decreased GFR sensed by macula sensa > increased renin release
Renin > activation of RAAS > increased water reabsorption
Thirst centre (hypothalamus)
Activation of thirst centre in the lateral hypothalamus (due to increased osmolality) > behavioural change to increase water intake
Feedback
The above systems work predominately on a negative feedback system
Examiner comments
28% of candidates passed this question.
This is a level 1 topic. An understanding as to how the body regulates water is crucial to the daily practice of critical care, this topic is well described in the major texts. This type of question lends itself to the basic template of sensor mechanisms, central processing and integration with effector limbs and feedback loops. However, high scoring answers require a quantification of responses and an introduction into how these processes are integrated and fine-tuned.
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Question 8, 2008 (1st sitting)
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Question 2
Question
Describe the pharmacology of lidocaine
Example answer
Name
Lidocaine (lignocaine)
Class
Amide anaesthetic / Class 1b antiarrhythmic
Indications
Local/regional/epidural anaesthesia, ventricular dysrhythmias, IV analgesia,
Pharmaceutics
Clear colourless solution (1%, 2%, 4%). Can come with/without adrenaline. Also available as cream/spray
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 ~1L/kg.
Crosses BBB
Metabolism
Extensive hepatic metabolism with some active metabolites
Elimination
Metabolites excreted in urine.
Half life ~90mins. Increased with adrenaline (SC). Reduced in cardiac/hepatic failure.
Special points
Examiner comments
71% of candidates passed this question.
The answers for this question were generally of a good standard. Lidocaine is a core drug in intensive care practice and thus a high level of detail was expected. This question was best structured using a standard pharmacology template (pharmaceutics, pharmacokinetics and pharmacodynamics). A small number of answers omitted any pharmaceutic elements. Another common error was the use of vague and imprecise statements. For example, many answers stated that the maximum dose (without adrenaline) is 3 mg/kg, without specifying that this is subcutaneous. The concept of the ratio of the dose required to produce cardiovascular collapse to that required to induce seizures (CC/CNS ratio) was often mentioned. However, in many cases this was conveyed simply as an abbreviated statement without any additional explanation leaving the examiner unsure as to whether the candidate understood the concept (and thus unable to award any additional marks). In addition, many candidates confused the order of this ratio (incorrectly referring to it as a CNS/CC ratio of 7). Lastly, few answers made specific mention of the narrow therapeutic index and the associated implications for use in the ICU.
If stroke volume remains the same, then increasing HR will increase CO
However, in a healthy person within physiological HRs (60-150), if there is no increase in physiological demand, altering HR has limited effects on CO as the stroke volume reduces
In extremes of HR, with increased metabolic demand, or pathology (e.g. poor contractility), altering HR will impact cardiac output
Stroke volume (SV)
Stroke volume = EDV - ESV, Normally ~70mls
Increased stroke volume = increased CO
Factors affecting stroke volume include
Preload
Myocardial sarcomere length just prior to contraction.
Cannot be measured, so approximated by EDV
Increased preload > incre
Factors effecting preload include
Ventricular compliance
Venous return
Valvular disease
Heart rate
Myocardial wall thickness
Atrial contractility
Afterload
External force required to be generated before the mycoardial sarcomere begins to shorten
Reduced afterload > increased SV > increased CO
Factors affecting afterload include:
Systemic vascular resistance
Outflow tract impedance
Transmural pressure
Myocardial wall thickness
Contractility
Intrinsic ability of the myocardial fibres to shorten/contract
Increased contractility = increased SV = increased CO
Factors effecting contractility include
Bowditch effect
Anrep effect
Tone
Heart rate
Ischaemia/drugs.
Examiner comments
65% of candidates passed this question.
Although the pass rate for this question was reasonably high the examiners commented on a lack of detailed knowledge within most answers for such a core component of our daily practice. Several candidates failed to provide a normal value and only few provided anything other than 5l/min. There was a general lack of detail, and at times, some confusion about the Frank Starling effect. Most candidates outlined the major determinants of stroke volume, although many were light on the determinants of each or incorporated incorrect facts. Several candidates did not mention HR as a determinant of CO
Good CSF, tissue, fluid penetration.
Poorly protein bound (10%)
Highly protein bound (90%). Negligible CSF/urine distribution.
VOD = ~1L /Kg
Metabolism
Not metabolised
Minimal hepatic metabolism
Elimination
Renal (unchanged 80%).
T 1/2 ~30 hours
Renal/faecal elimination.
T 1/2 = 15 days.
Special points
Monitoring: LFTs, drug interactions
Monitoring: renal function
Examiner comments
6% of candidates passed this question.
This question exposed an area of the syllabus neglected by the candidates. Answers were generally vague in detail with lots of incorrect facts and generally displayed a very limited knowledge. Antifungal agents are regularly used in critically ill patients either as treatment or prophylaxis. An understanding of the aspects of these drugs with respect to spectrum of activity, mechanism of action, specific PK and PD properties as well as potential side effects would have been the basis for this compare and contrast question. Examiners want to be convinced that the candidates understand the strengths and weaknesses of each drug and in which circumstances one agent might be used in preference to the other.
Write detailed notes on angiotensin, including its synthesis, role within the body and regulation
Example answer
Synthesis and regulation
Angiotensinogen
Peptide hormone continuously synthesised in the liver and is a precursor to angiotensin
Increased release in response to corticosteroids, oestrogens, thyroid hormones, AGT2 levels
Renin converts angiotensinogen to Angiotensin I
Renin is produced, stored, secreted from JG cells in kidney
Stimulated by reduced GFR, decreased Na/CL delivery to MD, sympathetic innervation
Inhibited by Angiotensin II (negative feedback)
Angiotensin converting enzyme (ACE) converts Angiotensin I to Angiotensin II
ACE is present in the capillary endothelial cells in the lungs (and renal endothelium)
There is also angiotensin III and IV which are the product of further cleavage by peptidases
These have similar effects to angiotensin II (but reduced potency)
The renin-angiotensin-aldosterone system (RAAS) exerts negative feedback on the release of renin, additionally increased BP and Na/Cl delivery will decrease renin secretion
Effects of angiotensin
Angiotensin I
Thought to be physiologically inactive, but acts as a precursor to Angiotensin II
Angiotensin II
Renal effects
Increases Na-H antiporter activity in PCT > increased Na/Water reabsorption
Vasoconstriction of afferent + efferent arterioles + contraction mesangial cells > reduced GFR + urine output
CVS effects
Binds AT1 receptors > vasoconstriction >increased SVR > inc. BP
Neurohormonal effects
Increases sensation of thirst through activation of hypothalamus > increased blood volume
Increases the release of ADH from the pituitary gland
ADH Increases water reabsorption by inserting aquaporins in the collecting ducts
Increases production and release of aldosterone from adrenal cortex
Aldosterone increases blood volume: Increases Na/Water reabsorption in DCT
Aldosterone increases blood pressure: by increasing blood volume, but also by direct vasopressor effects
Examiner comments
24% of candidates passed this question.
This question provided headings for the answer template. Good answers integrated the required facts from the appropriate chapters of the major texts. Most answers lacked detail surrounding the factors that increase or decrease angiotensin activity. Few answers provided any detail as to all the mechanisms through which angiotensin exerts it effects. A lot of answers focussed singularly on the vascular effects of angiotensin. Overall, there was often a paucity of detail, with vague statements and incorrect facts
Effected by contractions > increased intrauterine pressure > decreased flow
Uterine vascular resistance
The radial arteries of the myometrium are modestly effected by exogenous vasopressors, catecholamines
Compensates for the lack of autoregulation by increasing oxygen extraction
Examiner comments
49% of candidates passed this question.
There was a wide range of marks for this question with a few candidates scoring excellent marks. Those answers that scored well provided a comprehensive list of functions as well as an explanation as to the what, how and/or why of these functions. Poorer answers omitted some of the functions or failed to elaborate on them by providing only a limited list. The second component of the question was generally well outlined, most candidates provided some estimate of normal values at term and a simple elaboration regarding the factors that affect placental blood flow.
Outline how the measurement of the following can be used in the assessment of liver function (25% marks of each): 1) Albumin 2) Prothrombin time 3) Glucose 4) Ammonia
Example answer
Albumin
Albumin is a protein synthesized in the liver (half life ~3 weeks)
Normally 34-45g/L in the blood
With chronic liver dysfunction there is reduced synthesis > low albumin
Measures the rate of conversion of prothrombin to thrombin
Normal PT = 10-13 seconds
Most coagulation factors are synthesised by the liver
If synthetic function of the liver is impaired (e.g. by severe cirrhosis) there would be a prolonged prothrombin time.
If synthetic function of the liver is normal, but prothrombin time is prolonged, this would imply drug effect (eg. warfarin), consumptive coagulopathy, or VitK deficiency
Glucose
Essential energy substrate
Normal BGL = 4-6 for most people (physiologically varies with diet/time)
Liver is important for glucose homeostasis including glycolysis, glycogenolysis and gluconeogenesis
Liver failure may lead to both diabetes as well as hypoglycaemia
Blood glucose levels or neither sensitive, nor specific for liver dysfunction
Hypoglycaemia may be causes by numerous other conditions including pancreatic disorders, stress, drugs, diet/malnutrition, GIT absorption issues etc.
Ammonia
Ammonia is a nitrogenous waste product
Produced by amino acid metabolism, urea hydrolysis in the GIT and renal synthe
Normal level <30ug/L in adults
Normally transported to liver for conversion to urea via urea cycle > excreted kidneys
If liver is unable to metabolise ammonia > accumulates
Hyperammonaemia is relatively specific to cirrhotic liver disease (90% of cases)
Other causes include
Haematological disorders (e.g. myeloma)
Congenital defects in urea-cycle function
Drugs: e.g. valproate
Examiner comments
54% of candidates passed this question.
This was a new question and overall, most candidates provided some detail on each component as requested. Those answers that used a simple template for each section generally scored better than those who wrote in a paragraph style for each section. Areas expected to be covered included the following; a definition of the variable to provide context, a normal value and the range of influences that effect the variable both related to liver function and or extrinsic to the liver (attempting to introduce the concepts of sensitivity and specificity for each test). Stronger answers provided some context as to whether the variable was sensitive to acute or chronic changes in liver function and which synthetic/metabolic component of the liver the variable represented
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Nil
Question 8
Question
Describe the anatomy of the internal jugular vein including surface anatomy landmarks relevant to central venous line insertion.
Example answer
Internal jugular vein
Originates at the jugular bulb (confluence of the inferior petrosal and sigmoid sinus')
Exits skull via the jugular foramen with CN IX, X, XI
Descends inferolaterally in the carotid sheath (initially posterior > lateral to carotid artery with descent)
Terminates behind the sternal end of the clavicle where it joins with the subclavian vein to form the brachiocephalic vein
Variation in relation to carotid (e.g. anterior) in up to 1/4 cases
Ultrasound anatomy
Often lateral to carotid (not always) and often larger than carotid
Unlike carotid: Non pulsatile, thin walled, compressible
Doppler flows can also be helpful.
Surface anatomy
Identify triangle between the clavicle and two heads of SCM
Palpate carotid
Puncture lateral to carotid artery at 30 degree angle
Aim caudally towards ipsilateral nipple
Examiner comments
38% of candidates passed this question.
The overall pass rate for this question was poor considering how relevant this area of anatomy is in our daily practice. Better scoring answers used a template including a general description, origin, course and relations, tributaries and as requested in this question, the surface anatomy. Many answers that scored poorly only provided the briefest detail, were vague in their descriptions and incorrect with respect to the facts presented or imprecise with respect to the terminology used
Outline the classification and effects of beta-blocking drugs, including examples (50% marks). Compare and contrast the pharmacokinetics of metoprolol with esmolol (50% marks).
Example answer
Classification of beta blockers
All beta blockers are competitive antagnoists
Can be classified according to
Receptor selectivity
Non selective (B1 and B2) e.g. sotalol, propranolol
B1 selective e.g. metoprolol, esmolol, atenolol
A and B effects: labetalol, carvedilol
Membrane stabilising effects (inhibit AP propagation)
Stabilising e.g. Propanolol, metoprolol
Non stabilising e.g. atenolol, esmolol, bisoprolol
Intrinsic sympathomimetic activity
ISA e.g. labetalol, pindolol
Non ISA e.g. metoprolol, sotalol, propranolol, esmolol
Effects of beta blockers
B1 antagonism
Heart: decreased inotropy and chronotropy (decreased BP), decreased myocardial oxygen consumption, decreased AV nodal conduction
This was a two-part question with marks and thus timing of the answers given as a percentage. There are generally many ways to classify drugs within the same class. These are usually well described in the relevant recommended pharmacological texts. Receptor distribution throughout the body and the effect of the drug-receptor interaction are useful ways to organise systemic pharmacodynamic responses, as opposed to a list of organ systems with associated vague statements of interaction
Describe the ventilation / perfusion (V/Q) relationships in the upright lung according to West’s zones (40%). Explain the physiological mechanisms responsible for these relationships (60%)
Example answer
West zones
A way of describing the regional differences in alveolar, arterial and venous pressures in the lung
Initially Zones 1-3 described, with a 4th later added
Alveolus compresses arterial and venous flow. Hence there is ventilation but no perfusion
Leads to infinite V/Q (dead space)
Generally does occur under physiological conditions but can when
Alveolar pressure is very high (very high PEEP)
Arterial pressure is very low (shock)
West Zone 2
Pa > PA > Pv
Intermittent blood flow throughout cardiac cycle. PA acts as starling resistor
Seen in the lung apex > rib ~3
V/Q As high as 3.0
West Zone 3
Pa > Pv > PA
Blood flows continuously throughout the cardiac cycle
Majority of lung below ~Rib 3
V/Q approaches 0.3
West zone 4
Pa > Pi (intersitital fluid) > Pv > PA
With interstitial fluid acting as a starling resistor
Seen in pathological states e.g. pulmonary oedema
V/Q ratio (in upright person)
Perfusion (Q)
Increases from apex > base of lung
Due to the effects of gravity > increased hydrostatic pressure
Ventilation
Increases from apex > base of lung
Because of the vertical gradient of pleural pressure (-10cmH2O apex, -3cm base) the apices get less ventilation than the bases at normal lung volumes as they are less compliant
V/Q ratio
Because blood is denser than air, the effect of gravity is greater on perfusion than ventilation
At about the level of rib 3: V/Q ratio is approx 1.
Above rib 3 (West zone 1/2): V/Q > 1.0
Below rib 3 (West zone 3): V/Q < 1.0
Examiner comments
47% of candidates passed this question.
This is a core aspect of respiratory physiology, and a detailed understanding of this topic is crucial to the daily practise of intensive care. As such the answers were expected to be detailed. Strong answers included precise descriptions of the zones of the lung as described by West and related these to the V/Q relationship in the upright lung. Generally, most candidates scored well in this section. Diagrams were of varying value. However, an impression from the examiners was that candidates spent too much time on this first section and ran out of time for a detailed answer in the second section. The answers to the second section seemed rushed and were often lacking in detail with many incorrect facts. This question highlights the importance of exam technique preparation in the lead up to the written paper
Amiodarone can potentiate/interact with numerous other drugs, by displacing them from proteins, increasing their free fraction (e.g. phenytoin, warfarin)
PREGNANCY
Neurodevelopmental abnormalities
Risk of congenital hypothyroidism
Examiner comments
17% of candidates passed this question.
The question asked for a detailed account of the side effects of amiodarone, hence those candidates that just provided a list or outline scored less well. It was expected that candidates provide some detail of the side effect. Answers that scored well prioritised those relevant to ICU clinical practice. Many provided disorganised outlines of the side effects and frequently the cardiovascular side effects were poorly explained. Many candidates omitted the important drug interactions of amiodarone use and few candidates related the side effect profile to the duration of treatment
Explain the physiological factors that affect airway resistance
Example answer
Airway resistance
Equal to the pressure difference between alveoli and the mouth divided by the flow rate
Expressed as pressure per unit flow (cm.H2O.s)
FACTORS AFFECTING AIRWAY RESISTANCE
Type of flow
Laminar flow produces less airway resistance than transitional or turbulent flow
The type of flow depends on Reynolds number (Re)
<math display="inline">Re \; = \; \frac {2 \; r \; v \; p} {n}</math> Where r = radius, v=velocity, p=density, n=viscosity
Hence
Increase in density, velocity or radius = increased Reynolds number = more likely turbulent
Increased viscosity (n) = decreased Re = more likely to be laminar flow
Laminar flow occurs typically with Re <2000
Vessel (airway) radius
Based off Hagen-Poiseuille equation (<math display="inline">Resistance \; = \; \frac {8nl}{\pi r^4}</math>) the smaller the calibre of the airway the increased resistance.
Increased tone (e.g. bronchospasm or increased PSNS tone) narrows radius
Decreased internal diameter
E.g. due to sputum plugging/aspiration > decreased effective radius
External compression
E.g. tumour, pneumothorax > decreased radius
Length
Based off the H-P equation, increased length = increased resistance
Not seen in physiological conditions but can be altered for example with artificial ventilation
Dynamic airway compression
With forced expiration > increased intrapleural pressure
If IP pressure > airway pressure > collapse > decreased radius
Examiner comments
31% of candidates passed this question.
It was expected candidates cover the breadth of the factors that affect airway resistance. Generally, as a concept the type of flow (laminar vs turbulent) was answered well by most candidates, however many failed to mention the other factors that affect airway resistance. Airway diameter as a primary determinant of airway resistance was commonly omitted. Better answers which covered the factors affecting airway diameter classified them broadly and included examples such as physical compression/external obstruction, broncho-motor tone and local cellular mechanisms. Some answers did not explain these factors in enough detail and often with incorrect facts
Describe the factors that affect mixed venous oxygen saturation
Example answer
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
Normally ~75%
Provides better idea of whole body venous O2 sats (blood from SVC, IVC and coronary sinus)
Factors affecting SmvO2
SmvO2 is a balance between oxygen delivery and oxygen consumption
Oxygen delivery (DO2) = cardiac output (CO) x oxygen content of arterial blood (CaO2)
CaO2 is dependant on the arterial oxygen saturation, partial pressure of oxygen and the loading ability of Hb (thus the PCO2, temperature, H+ concentration)
e.g. exercise = increasing consumption = Decreased SmvO2
Pathological conditions
e.g. fever/burns = increased consumption = decreased SmvO2
e.g. cyanide toxicity, hypothermia = decreased consumption/utilisation = increased SmvO2
Evidence
No evidence to support targeting ScvO2 or SmvO2 saturations at present
Examiner comments
49% of candidates passed this question.
Mixed venous oxygen saturation is used as a surrogate marker for the overall balance between oxygen delivery and oxygen consumption. A good answer stated this, described the importance of where it is measured and went on to describe the various factors that affect oxygen delivery and consumption. Descriptions of the factors that affect oxygen saturation of haemoglobin, partial pressure of oxygen in the blood and position of oxygen-haemoglobin dissociation curve were necessary to score well. Important omissions were factors that increased and decreased oxygen consumption. While many candidates were able to correctly write the equations for oxygen content and oxygen flux, they then failed to describe how the variables within these equations were related to mixed venous oxygen saturation.
Online resources for this question
CICM Wrecks
Deranged Physiology
Jenny's Jam Jar
Similar questions
Question 10, 2008 (1st sitting)
Question 19, 2017 (1st sitting)
Question 8, 2019 (1st sitting)
Question 14
Question
Describe the production, action and regulation of thyroid hormones.
Example answer
Overview
Thyroid gland produces and secretes two hormones
T4 (thyroxine) = 93%
T3 (tri-iodothyronine) = 7%
Production and secretion
T3/T4 synthesised in thyroid follicles
Iodide is taken into thyroid follicles via secondary active transport and oxidised to iodine by thyroperoxidase
Thyroglobulin is synthesized in the follicular cell and is secreted into follicular cavity where it combines with iodine to form DIT and MIT, which subsequently couple to form T3 or T4
T3/T4 are secreted from the vesicles (thyroglobulin is cleaved off in the process)
Regulation
Increased production
Increased TSH (from anterior pituitary) > increased T3/T4 production and release (from thyroid)
TSH is increased by TRH (produced by paraventricular nucleus in hypothalamus)
TRH is stimulated by numerous factors including low T3/4, cold, hypoglycaemia, pregnancy
Decreased production
Secretions are controlled via negative feedback loop on the hypothalamic-pituitary-thyroid axis
Thus increased T3/T4 > decreased TSH (from pituitary) and decreased TRH (from hypothalamus)
Transport / half life
Transported in blood bound to albumin, thyroxine binding globulin
Both are >99% protein bound
T3 has half life 24 hours
T4 has half life 7 days
Functions
T3/T4 act on thyroid receptors in the cell nucleus > increased gene transcription + protein synthesis
T3 is 3-5x more active than T4 (though less abundant)
Effects on organ system
CVS
Increased HR, inotropy, CO
Decreased SVR
RESP
Increased minute ventilation (due to increased CO2 production)
CNS
Increased: neuroexcitability, tremors
Decreased: depression, psychosis
MSK
Increased osteoblast activity
GIT
Increased GIT motility
METABOLIC
Increased basal metabolic rate
Increased carbohydrate, fat and protein metabolism
Examiner comments
81% of candidates passed this question.
This question was divided in three sections to help candidates formulate an answer template, which for the most part was answered well. Most answers included a detailed description of the production and regulation of thyroid hormones, including the importance of negative feedback. A brief description of the action of thyroid hormones on intracellular receptors, and a system-based description of physiological effects, including CHO, protein and fat metabolism was expected.
Classify and describe the mechanisms of drug interactions with examples.
Example answer
Classification of drug-drug interactions
Example
BEHAVIOURAL
- One drug alters behaviour of patient for another
- A depressed patient taking an antidepressant may be more compliant with other medications for unrelated conditions
PHARMACEUTIC
- Formulation of one drug is altered by another before administration
- Precipitation of thiopentone (basic) and vecuronium (acidic) in a giving set
PHARMACOKINETIC
Absorption
Bioavailability of bisphosphonates is reduced when co-administered with calcium as the drugs interact to form insoluble complexes
Distribution
Valproate and phenytoin compete for the same transport protein binding sites > decreased protein binding phenytoin > increased effect
Metabolism
Macrolides reduce metabolism of warfarin by outcompeting it for similar metabolic pathways (CYP450 enzymes) > increased duration of effect
Elimination
Probenecid decreases the active secretion of B-lactams and cephalosporins in renal tubular cells by competing for transport mechanisms > decreased elimination of B-lactams / cephalosporins
PHARMACODYNAMIC
Homodynamic effects
Drugs bind to the same receptor site (e.g. naloxone reverses the effects of opioids by outcompeting for the opioid receptor sites)
Allosteric modulation
Drugs bind to the same receptor (GABA) but at different sites (e.g. barbiturates and benzodiazepines) > increased effect
Heterodynamic modulation
drugs bind to different receptors but affect the same second messenger system (e.g. glucagon reverses the effects of B-blockers by activating cAMP)
Drugs with opposing physiological actions (but different biological mechanisms)
e.g. GTN vasodilates via guanyl cyclase-cGMP mediated vasodilation, while noradrenaline vasoconstricts via <math display="inline">\alpha</math> agonism
Examiner comments
54% of candidates passed this question.
This question has been asked previously, the answer template expected some description rather than a list of drug interactions. Generally, examples were provided for each type of interaction. The examiners reported too many vague, factually incorrect descriptions of the mechanisms and in some cases a very limited classification.
Antipsychotic actions thought to be mediated by blockade of dopamine (D2 > D1) receptors particularly in the limbic system. Also demonstrate weak antagonism of H1, mACh receptors
Effects
CNS: apathy, decreased agitation, sedation
CVS: QT prolongation / TdP
GIT: anti-emetic
MET: weight gain, diabetes, hyperChol
Other: neuroepileptic malignant syndrome, extrapyramidal side effects (dystonia, akathisia, parkinsonism, TD)
HAEM: leukopaenia
RESP: respiratory depression in large enough doses
Pharmacokinetics
Onset
Peak effects after 3 hours (PO)
Absorption
80% PO bioavailability
Distribution
>90% protein bound
VOD = 20L/kg
Metabolism
Hepatic > inactive metabolites
Elimination
Renal (major) and faecal (minor) excretion of metabolites
T 1/2 = ~24 hours (longer in IM, shorter in PO)
Special points
Examiner comments
28% of candidates passed this question.
Excellent answers were able to provide a classification of antipsychotics based on either typical/atypical or first/second generation categories, provide examples of each and identify key differences in mechanism and effects. They also distinguished between butyrophenones and phenothiazines within the typical antipsychotic group. Haloperidol was identified as a butyrophenone, with description of pharmaceutics, dose and route, as well as pharmacodynamics and pharmacokinetics. Key adverse effects were detailed, focusing on those specific to haloperidol, including a description of different types of extrapyramidal symptoms and QT prolongation/ torsades de pointes.
Amplifies the low signal (~1mV) through differential amplification
Filters out noise/artefact
High input impedance - filters out EMG signal and mains interference
Low pass filtering - eliminates movement artefact
Monitor/output device
Displays/prints/records the trace
Artefact and error
Machine
Incorrect filtering settings
ECG monitoring mode: Strong filter setting to focus on rhythm, reduces artefact
Diagnostic mode: Lower filtering setting to allow for subtle changes in ST segments (greater resolution at expense of noise)
Cabling/Circuit
Incorrect lead placement --> errors with augmented leads, and interpretation --> correct
Interference with electronics (e.g. ventilators, dialysis machines) --> limit exposure
Damaged/broken cables --> replaced
Patient
Excessive movement or motion artefact (movement, shivering, seizure)
Rewarm, low pass filtering, place over bony prominences
Poor contact due to things such as hair, lotions, etc.
Cleaned with alcohol wipe / shaved to improve contact
Examiner comments
46% of candidates passed this question.
Excellent answers described the function of the ECG device and its components. Components include electrodes, which form leads (unipolar and bipolar), the amplifier and an output device. The process of amplification and filtering (e.g., high and low pass filters), as well as monitoring and diagnostic ECG modes were described. A comprehensive list of ways to reduce artefacts, including strategies to address both patient and equipment factors was generally provided.
Effect: ipsilateral eyelid movement (early response) followed by bilateral blink (late response)
Oculomotor reflex (Vestibulo–ocular reflex)
Sensation: head rotation (angular acceleration)
Sensor: semi-circular canals and otoliths in inner ear
Afferent: cranial nerve VIII
Integrator: vestibular nuclear complex (medulla and pons)
Efferents: cranial nerves III, IV and VI
Effect: activation of recti muscles (depending on rotation) to maintain visual focus
Gag reflex
Stimulus: sensation to posterior pharyngeal wall
Afferent: cranial nerve IX
Integrator: NTS > nucleus ambiguus
Efferent: CN X
Effects: Contraction of pharyngeal muscles
Examiner comments
43% of candidates passed this question.
This is a fact-based question with little integration of knowledge required. Those candidates who synthesised their knowledge into a succinct and precise description of afferent and efferent pathways with a description of the various sensor and integrator components scored very high marks. A good working knowledge of all the cranial nerve reflex pathways are crucial to the practise of intensive care medicine. Marks were not awarded for any anatomical description related to these pathways.
Online resources for this question
CICM Wrecks
Deranged Physiology
Jenny's Jam Jar
Similar questions
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Question 19
Question
Outline the process of fibrinolysis (40% marks). Write short notes on the indications, mechanism of action, pharmacokinetics and side effects of tranexamic acid (60% marks).
Example answer
Fibrinolysis
Process by which fibrin (within blood clots) is broken down by plasmin into fibrin degradation products
Normal physiological process as part of wound healing and is important for keeping vessels patent
Steps
Plasminogen (b-globulin) is produced in the liver
Plasminogen is trapped in fibrin meshwork during initial clot formation
Plasminogen can be converted by plasminogen activators (serum protease) into plasmin
Intrinsic: Main physiological activator is tissue plasminogen activator which is released from injured endothelial cells (but is a slower process than coagulation to allow healing to take place)
Extrinsic: urokinase, streptokinase, recombinant tPA can increase activation of plasminogen > plasmin > increased fibrinolysis
Clear colourless solution (100mg/ml) for injection (IV)
Routes of administration
PO, IV, IM
Dose
0.5 - 1 g (slow IV push), followed up by infusion of 1g over 8 hrs if needed
pKA
Pharmacodynamics
MOA
Competitive inhibition of the activation of plasminogen into plasmin by binding to lysine binding sites on plasminogen
Effects
Decreased fibrinolysis > decreased bleeding
Side effects
HAEM: Prothrombotic complications in those patients with risk factors
GIT: nausea, vomiting CNS: seizures and dizziness (dose related)
Pharmacokinetics
Onset
Immediate (IV), 1 hour (IM), 2 hours (PO)
Absorption
PO bioavailability = 50%, IM bioavailability 100%
Distribution
Protein binding: very low (<5%)
VOD = 0.3L / kg
Metabolism
Minimal hepatic metabolism
Elimination
Renal elimination of active drug (95% unchanged)
T 1/2 = 2hrs (IV), 10 hrs (PO)
Special points
Dose reduce in renal failure
Examiner comments
30% of candidates passed this question.
The relative allocation of marks and thus time to be spent on each component was delineated by the relative percentages in the question. The first part of the question required a step-by-step outline of the fibrinolytic pathway with mention of the regulatory processes. Tranexamic acid is an important drug in the practice of intensive care and the question provided the headings under which to answer the question. The detail surrounding the keys aspects of this drug with respect to its use in critical care were often vague and underappreciated.
Describe the physical principles of haemodialysis and haemofiltration, including the factors affecting clearance (80% marks). Outline the key components of renal replacement fluids (20% marks).
Example answer
Dialysis
Separation of particles in a liquid, based on their differential ability to pass through a membrane
Main mechanisms: haemodialysis, hemofiltration, combination of above
Main indications: acidosis, electrolyte derangement, intoxication, fluid overload, ureamia,
Haemodialysis
Utilises principle of diffusion
Spontaneous movement of a substance from area of high > low concentration
Movement is dependant on Fick's law (thus temp, size, concentration, distance etc)
Process
Blood is pumped through an extracorporeal dialysis circuit
Dialysate flows in a counter-current direction (maintains concentration gradient)
Blood is separated from dialysate via semipermeable membrane (does not mix)
Movement of molecules then diffuses according to Ficks law.
Useful for clearance of small molecules, cannot clear larger molecules
Haemofiltration
Uses principle of convection and solvent drag
Elimination of materials is via bulk flow and independent of concentration
Clearance is dependant on starling forces
Process
Blood is pumped through extracorporeal dialysis circuit
A transmembrane pressure is applied to the blood side of a semi-permeable membrane
Plasma is filtered across membrane and solutes (via drag) are eliminated as effluent.
Renal replacement fluid is added to patient blood to restore volume, buffers, and normal haematocrit
Can clear small-medium sized molecules
Factors effecting clearance
Drug factors
Protein binding
Small molecules bound to large proteins (e.g. aspirin bound to albumin) cannot be cleared
Size/molecular weight
Smaller molecules are more readily dialysed
Volume of distribution
Drugs with large Vd (e.g. barbituates) cannot readily be cleared as they rapidly redistribute
Dialysis factors
Haemodialysis
Blood / dialysate flow rate
Dialysate composition
Haemofiltration
Blood / effluent flow rate
Transmembrane pressure
Prefilter dilution
Sieving coefficient
Renal replacement fluids
5000ml bag, warmed to body temperature
Contains
Electrolytes
Na = isotonic
K, Mg, Phos, Ca = variable
Buffers
Bicarbonate (predominately)
Can also use lactate, citrate
Nutrients (i.e. gluc)
Sterile water
Osmolarity ~285
Dose varied depending on degree of fluid removal desired
Examiner comments
28% of candidates passed this question.
A brief description of the underlying mechanisms of dialysis and hemofiltration was required. Diffusion, the predominant mechanism in haemodialysis, involves movement of solute down the concentration gradient across the semipermeable membrane. This concentration gradient is generated and maintained by counter current movement of dialysate and blood. In hemofiltration the predominant mechanism is convection and solvent drag of the solute across the semipermeable membrane by application of transmembrane pressure. The filtrate is then replaced by replacement fluid. Small molecules are effectively removed by dialysis whereas hemofiltration can remove small and middle molecules. Various factors that impact clearance in haemodialysis and haemofiltration were expected separately. Constituents of replacement fluid should have included three broad headings of electrolytes, buffer and sterile water. Many answers lacked the details of how counter current mechanisms help, the difference in the two modalities in regard to clearance of molecules, how clearance is impacted by protein binding and volume distribution, sieving coefficient of the membrane and flow rates of blood and dialysate (or effluent) flow. The constituents of replacement fluid lacked details of various types of electrolytes, the common buffers and the strong ion difference.
Metabolised by MAO (mitochondria) and COMT (liver, blood, kidney) to VMA and metadrenaline
Elimination
T 1/2: ~2 mins (due to rapid metabolism)
Metabolites (above) are excreted in the urine
Examiner comments
90% of candidates passed this question.
Adrenaline is a level 1 drug and is commonly used in intensive care. A comprehensive explanation of the drugs MOA, PK, PD and side effect were expected. Candidates who scored well generally provided a factually accurate, detailed and well-structured answer. Overall, the quality of answer provided for this question was of a high standard.
This is a core topic within respiratory physiology. There was a very low pass rate for this question. Expected components of the answer included: a definition of WOB as a product of pressure and volume or force and distance including the units of measurement; followed by a detailed explanation of the following three broad components – elastic resistance, viscous resistance and airflow resistance. Further marks were awarded to situations where the energy for expiration increases beyond stored potential energy as well as the impact of respiratory rate and tidal volume on different aspects of the WOB. For example, the changes in TV will have relatively greater impact on the elastic component, whereas RR will impact the resistance component. Additional marks were awarded for describing the efficiency of breathing. A common area where candidates missed out on marks was producing a diagram of WOB without a description; many diagrams were often incorrectly drawn or had no axes labelled. There were many incorrect definitions or respiratory equations provided without any link to the written answer. Factual inaccuracy and limited depth of knowledge were also prevalent in poorly performing answers. Marks were not awarded for a description of the control of breathing.
Outline the formation, structure, and function of the platelet.
Example answer
Formation/fate
Produced via thrombopoiesis
Within the bone marrow, common myeloid progenitor cells differentiate into megakaryocytes
Megakaryocytes are the largest cell of the bone marrow (50-150um), have multiple (up to 8) nuclei. They produce pro-platelets in their cytoplasm which break up into numerous smaller functional platelets. Each megakaryocyte produces ~5000 platelets each
Thrombopoiesis takes ~10 days
Thrombopoietin (produced primarily in the liver) stimulates the differentiation and release of plts
Process regulated by negative feedback loop based on platelet count
Normally 150-400 x 10^9/L
Lifespan is 7-10 days
Utilised during clotting or removed by the reticuloendothelial system in the spleen or liver
Structure
Not true cells, but fragments of the Megakaryocyte cytoplasm
1-4 um in size, Irregular, No nucleus.
External glycocalyx later
Contain:
Mitochondria
Dense granules (ATP, ADP, calcium)
Alpha granules (vWF, thrombin)
Contractile elements (microtubules)
Function
Main function of platelets is haemostasis
Platelets are important for formation of the platelet plug (primary haemostasis)
Platelet adhesion
Damage to blood vessel wall exposes vWF in the subendothelium
Glycoprotein receptor complex (GP1b-IX) on platelets bind to vWF (adhesion)
Platelet activation
When exposed to Tissue Factor, collagen, and vWF the platelets become activated
Activated platelets
Change shape (Swell, become irregular, develop pseudopods) to enable aggregation
Release molecules (Thromboxane A2, ADP, Serotonin) which activates further platelets + vasoconstricts
Platelet aggregation
Activated platelets bind to fibrinogen and vWF to form a soft platelet plug
Platelets are also central to the cell based model of secondary haemostasis
Initiation (less relevant to platelets)
Amplification
Surface of activated platelets is primed with factors V, VIII, XI
Small amount of thrombin produced during initiation activates V, VIII and XI
XIa activates IX to IXa, which leads to formation of tenase complexes (accelerate thrombin production at platelet surface)
Propagation
Begins with formation of tenase complexes on platelet surfaces (IXa-VIIIa)
Leads to increased rate of Factor X activation
The large amounts of Xa interacts with factor Va forming prothrombinase complex (Va-Xa)
Va-Xa catalyses the conversion of prothrombin to thrombin
Examiner comments
79% of candidates passed this question.
This question was divided in three sections to help candidates formulate an answer template. The first section required a brief outline of the formation of platelets from pluripotent stem cells via megakaryocytes. The second section required an outline of platelet structure highlighting the special features such as, an absence of a nucleus, the presence of an external glycocalyx layer, specific surface receptors, contractile proteins, dense tubular system and granules. The third section was about platelet function where the expected focus was on the role of platelets in haemostasis. This required outlining the mechanism of platelet plug formation by adhesion-activation-aggregation, interactions with the coagulation cascade and role of platelets in clot contraction as well as fibroblast invasion. Although many candidates were able to answer the first section reasonably well, there was a noticeable knowledge deficit in the latter two sections. A significant proportion of answers had missing information on platelet structure and lack of structure in outlining platelet function
Outline the dose (10% marks), composition (60% marks) and side effects (30% marks) of total parenteral nutrition (TPN).
Example answer
Overview
TPN is the delivery of nutrients into the venous circulation to replace enteral requirements
Indications
Patients who are unable to be fed via enteral route for prolonged periods of time (e.g. >72 hours)
May include patients who fail trial of enteral feeding or other contraindications (e.g. GI obstruction, severe pancreatitis, short gut syndromes)
Daily nutritional requirements (major)
Nutrient
Requirement (kg/day)
H2O
30mls
Energy
25-30 kcal
Protein
1g (higher in critically ill, 1.5g)
Glucose
2g
Lipids
1g
Na
1-2 mmol
K
1mmol
Ca / Mg
0.1mmol
PO4
0.4 mmol
Note
Requirements vary according to physiological (e.g. age, gender, body size, activity levels) and pathological (e.g. burns, sepsis, renal failure, hepatic failure) factors
Composition of TPN (note many formulations of this)
Glucose
Typically supplies around 60-70% of daily caloric needs (~1400KCal)
Typically 50% dextrose used (3.4 kCal/mil - 824mls)
Lipid
Typically supplies around 30-40% daily caloric needs (~600Kcal)
Can be olive oil, soybean, fish oil based
Protein (Amino acids)
Will contribute to energy source + provides essential amino acids
L-amino acids used only
Typically 1.5g/kg/day in critically ill (~100g protein / day)
Electrolytes (Na, K, Mg, Ca, Cl, PO4)
TPN solutions can come with/without electrolytes and adjusted
Vitamins, trace elements
Micronutrients are added in appropriate amounts to the bag for adequate daily intake
Thiamine, folic acid and vitK are vulnerable to depletion and additional may be needed
Water
In solution, though insufficient for daily requirements
Hyperosmolar solution due to above nutrients
Side effects / complications
Delivery device / vascular access related
Infection, pneumothorax, thrombosis, air embolism
Fluid/elextrolyte disturbances
Fluid overload
Electrolyte derrangements, shifts and refeeding syndrome
Acid base disturbances
Metabolic disturbances
Hypoglycaemia, hyperglycaemia (dose related issues due to over/under feeding)
Hyperlipidaemia
Examiner comments
59% of candidates passed this question.
The pharmacology of enteral and parenteral nutrition is a level 1 topic in the first part syllabus. The TPN dose in terms of daily calorie and other nutritional requirements were key expectations in first part of the question. A detailed list of all macro and micronutrients was required under TPN composition. Expected information about macronutrients were their forms in the TPN solution (e.g., carbohydrate in the form of glucose, protein in the form amino acids), their relative calorie contributions and their essential components (e.g., the names of the essential amino acids). Identification of potential variability in composition and dose based on specific patient factors scored extra marks. Side effects included metabolic derangements (refeeding syndrome, over or under-feeding, hyperglycaemia, hyperlipemia), biochemical disturbances (fluid and electrolyte imbalances), organ injury (liver, pancreas) and vascular access related complications. Limited breadth and depth of information as well as incorrect facts were prevalent in the answers that scored lower marks.
TV regurg > increased CVP (retrograde transmission of RV systolic pressure)
TV stenosis > increased CVP (increased resistance to RV inflow)
Intrathoracic pressure
ITP is transmitted to the central venous compartment
Thus, increased PEEP, IPPV, or a tension pneumothorax will lead to increased CVP
Measurement technique
Level of the transducer will clearly influence the CVP measured
Examiner comments
57% of candidates passed this question.
This question examined a core area of cardiac physiology and measurement. Considering this, candidates overall, scored poorly in this section. There was a common misunderstanding around the relationship between cardiac output and CVP. A decrease in cardiac output (e.g. due to either decreased stroke volume or heart rate) will cause an increase in CVP as blood backs up in the venous circulation, increasing venous volume as less blood moves through to the arterial circulation; the resultant increase in thoracic volume increases central venous pressure. Several candidates confused the direction of their arrows, for example "increased right atrial compliance increases CVP". Double negatives were used by several candidates which then resulted in the incorrect relationship described. (e.g., "arrow down compliance and arrow down CVP"). The measurement section should have included an explanation of the components of an invasive pressure monitoring system relevant to the measurement of CVP.
Describe the pharmacology of vecuronium, including factors that prolong its action of neuromuscular blockade.
Example answer
Name
Vecuronium
Class
Aminosteroid
Indications
Muscle relaxant; intubation, control of ICP, assist ventilation,
Pharmaceutics
Potentially unstable in solution
Comes in powder (10mg), dissolved in water (5ml) for use
Routes of administration
IV
Dose
Intubation: 0.1mg/kg
ED95
Pharmacodynamics
MOA
Non depolarising muscle relaxant;
Competitive antagonism of ACh at N2 receptors on PSM of NMJ
Effects
MSK: NMJ blockage (paralysis)
CVS: nil
RESP: Apnoea
Side effects
MSK: prolonged use can lead to myopathy
Rare for histamine release (anaphylaxis, hypotension)
Pharmacokinetics
Onset/duration
90-120s; 30-45 minutes
Absorption
IV only
Distribution
Doesn't cross BBB; VD 0.23L/kg
Metabolism
20% hepatic de-acetylation
Elimination
70% biliary, 30% urinary
Reversal
Can be reversed with sugammadex
Factors prolonging action
Electrolyte disturbances
Hypokalaemia, Hypermagnesemia and hypocalcaemia potentiates non depolarising NMBA
Acidosis
Increased affinity for ACh receptor
Hypothermia
Reduced metabolism of muscle relaxant > prolonged effects
Hepatic/renal disease
Prolonged metabolilsm/elimination of active metabolites
Drug interactions
e.g. lithium, diuretics, volatile anaesthetics, aminoglcosides
Examiner comments
13% of candidates passed this question.
Vecuronium is a commonly available and regularly used amino-steroid neuromuscular blocking agent. It is a level 1 drug in the 2017 syllabus. A simple template utilising the headings; pharmaceutics, PK, PD, uses in ICU and adverse reactions with associated relevant important facts would have scored well. Expected information regarding the factors prolonging neuromuscular blockade included electrolyte abnormalities, drug interactions and patient factors. Overall, the level of understanding and knowledge demonstrated in the answers was below an expected standard for a level 1 drug.
Arises from abdominal aorta immediately inferior to coeliac trunk (L1)
Multiple branches (15-20) which join 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
48% of candidates passed this question.
This question was answered best if the main arteries and veins were discussed first and then their corresponding supply outline in reasonable detail. Very few candidates were able to achieve this. Listing the names of vessels with no context and in a random non-sequential order did not attract many marks. The physiology of the blood supply to the liver also did not attract marks.
Describe renal handling of potassium (60% marks), including factors that may influence it (40% marks).
Example answer
Renal handling of potassium
Potassium is freely filtered at the glomerulus
Serum K = 4.2mmols/L, with 180L filtered / day (assuming GFR 125mls/min)
Thus most of filtered K needs to be reabsorbed in the kidney
Proximal convoluted tubule (PCT)
~60% of K reabsorbed
Reabsorbed passively by solute drag (coupled to water reabsorption) + concentration gradient
Water absorption is driven by the Na/K ATPAse on basolateral membrane > drives Na reabsorption
Loop of henle (LOH)
30% reabsorbed in thick ascending LOH
NK2Cl cotransporter drives transcellular reabsorption (via basolateral K channels) + paracellular reabsorption (due to negative charge generated by Cl reabsorption)
Active/secondary active transport
DCT + CD
0-10% reabsorbed
Secretion and absorption
Principle cells in DCT and CD: secrete potassium
Type A intercalated cells: reabsorb potassium
Net effect depends on the K state at the time
With normal intake or excessive intake, net effect is secretion
With low intake the net effect is reabsorption
Regulation / factors influencing renal handling K
Aldosterone
Increases Na-K ATPase activity primarily in the principle cells > increasing secretion of K
Vasopressin
Increases ROMK channels, increasing K secretion (balanced by decreased urinary flow rate)
Acid base disturbances
Metabolic alkalosis
Potassium secretion increases (increased Na/K ATPase activity due to low H+)
Metabolic acidosis
Potassium secretion decreases (opposite of above)
K intake
Increased intake > Increases ROMK channels > increasing K secretion
Examiner comments
33% of candidates passed this question.
This question covers a core physiology topic. The detail required is well described in the recommended reference texts. Generally, this question was poorly answered. From an answer template perspective, a "describe question" in this context involves both the stating the relevant potassium handling mechanism and then giving a description of how it occurs and how this system is regulated. Many answers that scored poorly simply listed sites of potassium handling but excluded the details surrounding the specific receptors and channels involved as well as the processes that exist to perpetuate and regulate these biological processes. Simple identification as to whether the potassium was being secreted or reabsorbed as well as the location as to where this may occur within the nephron, were often not specifically detailed or used interchangeably. Such answers scored poorly
59% of candidates passed this question. This question was relatively well answered by most candidates. There was significant variation in the temperatures expressed as normal and few candidates mentioned CORE temperature as a concept. Several candidates gave a detailed description of thermo-neutrality for which there were no marks.
How does warfarin exert its pharmacological effect (40% marks)? Write brief notes on the pharmacology of the agents that can be used to reverse the effects of warfarin (60% marks).
Example answer
Name
Warfarin
Class
Oral anticoagulant
Indications
Systemic anticoagulation, e.g. in prophylaxis/treatment of thromboembolism
Pharmaceutics
Racemic mixture of two enantiomers R and S, with the S isomer more biologically active.
Routes of administration
Oral
Dose
Varies; titrated to INR generally
Pharmacodynamics
MOA
Inhibits the synthesis of vitamin K dependant clotting factors (II, VII, IX, X).
Specifically, inhibits vitamin K epoxide reductase (VKORC1) from converting VitK from the oxidised to reduced form, which prevents carboxylation (activation) of clotting factors listed above (as well as protein C and S)
Effects
Anticoagulation
Side effects
Haemorrhage, teratogenicity (1st trimester), foetal haemorrhage (3rd trimester), drug interactions
Pharmacokinetics
Onset
Peak onset is 72 hours (as existing clotting factors not affected by warfarin)
Absorption
100% oral bioavailability
Distribution
99% protein bound, small VD 0.14L/Kg
Metabolism
Complete hepatic metabolism
Elimination
Renal elimination of metabolites
Reversal
Vitamin K, FFP, Prothrombinex, cessation+time
Reversal (in more detail)
Cessation + time
Stopping warfarin, will lead to normalisation of the INR generally in 4-5 days (but varies according to initial INR, comorbidities etc)
Mechanism: drug washout
Con: slow, risk of bleeding
Pro: decreased risk thrombotic events from over/rapid correction
Vitamin K
can be given IV/IM/PO
Higher doses, IV doses can reverse more rapidly
Mechanism: replenishes the substrate
Fresh frozen plasma
Mechanism: Contains all necessary clotting factors - hence rapid reversal
Blood product, with all the risks associated with this (fluid overload, infection, allergic responses)
Dose: 2-4 units (varies)
Con: require crossmatch, time for thawing etc
Prothrombinex
Mechanism: Contains factors II, IX, X (Aus) 500IU each- hence immediate reversal
Dose: 25-50 u/kg
Pro: immediate effects, smaller fluid volume, immediately available for use
Con: Factor 7 absent, expensive
A general approach, adapted from Red Cross Blood Service
Not bleeding
INR not too high (<4.5) and/or low bleeding risk = expectant management
INR high >4.5 and/or moderate-high bleeding risk = oral/IV Vit K
Bleeding
Life threatening: IV Vit K 10mg , Prothrombinex 50u/kg (or FFP if not available)
Clinically significant: IV VitK 5-10mg, Prothrombinex 25u/kg (or FFP if not available)
Minor bleeding: IV VIt K
Examiner comments
43% of candidates passed this question.
Warfarin is listed as a level 1 drug in the 2017 syllabus and as such a detailed knowledge of its mechanism of action would be expected from candidates sitting the exam. The reversal agents for warfarin are collectively classed as level 2 drugs and hence the knowledge required would be at a write short notes level. The following topics were expected: what drugs may be used, how they work, in what dose, any common side effects, why/when would one be used in preference to others etc. The use of reversal agents for warfarin is a common practice in ICU. Generally, answers demonstrated a lack of a precise and detailed knowledge with respect to warfarin’s mechanism of action and had a very superficial knowledge with incorrect facts regarding the reversal agents
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
Include haemoglobin (150g/L) and plasma proteins (70g/L)
Hb has pKa of 6.8. Weak acid (HHb) and weak base (KHb)
H+ binds to the histadine residues on imadazole side chains, the HCO3 diffuses down concentration gradient into ECF
Hb is quantitatively 6 times more important than plasma proteins, as the concentration is double and there are three times as many histadine residues in Hb
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
57% of candidates passed this question.
This is a core physiology topic; a detailed knowledge of buffering and the available buffer systems is crucial to ICU practice. A candidate presenting for the first part exam should have a detailed understanding of all aspects of the buffer systems. Higher scoring answers provided both technical details of the buffer systems, the context for their normal function and their relative importance. Efficient answers dealt with the buffers by chemical rather than by site, but many answers categorising buffers by site also scored well. Many low scoring answers simply failed to provide detail, some provided incorrect information. Very few candidates demonstrated an understanding of the isohydric principle
Oxidation > demethylation
Active metabolites: noroxycodone, oxymorphone
Elimination
Renal elimination
Active metabolites
T 1/2 = 2-4hrs (IR)
Reversal
Naloxone (100mcg IV boluses, PRN 3 minutely)
Examiner comments
54% of candidates passed this question.
There were many exceptional answers which provided extensive detail on the drug. The best of these gave context for the drug characteristics, such as by referring to oxycodone relative to other opioid drugs that might be chosen, or to considerations for safe and effective administration. Some answers, however, provided generic information on opioid drugs, which could not gain all the available marks.
Few candidates described cell types as chromophils and chromophobes. There were many errant references to chromaffin cells which are found mainly in the adrenal medulla, and to staining on H&E. Chromophil cells stain by absorbing chromium salts. Few candidates mentioned that the hormones secreted by the anterior pituitary are peptides. Most candidates outlined the hypophyseal-portal system well. Knowledge of TSH and ACTH control and target organ effects were good. Similar knowledge for LH, FSH, PRL and GH was much more sporadic.
Severe NAGMA, alkalinisation of urine (salicylate toxicity), hyperkalaemia, TCA overdose (Na channel blocking effects)
Pharmaceutics
Tablet (varying doses e.g. 300mg)
Clear colourless solution (various concentrations e.g, 4.2%, 8.4%) which can be given hypertonic or isotonic
Routes of administration
PO, IV
Dose
1mmol/kg IV = 1ml/kg of 8.4% (cardiac arrest due to hyperK)
Pharmacodynamics
MOA
Dissociates into Na and HCO3. The HCO3 functions as a buffer in the bicarbonate-carbonic acid buffering system (raising pH). The Na increases the strong ion difference in plasma (raising pH)
Incompatible with calcium /magnesium salts (precipitates)
Examiner comments
29% of candidates passed this question.
This question was best answered with a structured approach as per any pharmacology question. It nonetheless required good understanding of various aspects of physiology. Many candidates failed to gain marks by omitting to mention facts which could have been prompted by a defined structure. A good response mentioned the pharmaceutic features including formulation and the hypertonicity of IV bicarbonate, pharmacodynamics including indications for use, mode of action, adverse effects (systemic and local), pharmacokinetics and dose. Pleasingly a few candidates stated that sodium bicarbonate’s mechanism of action to cause alkalosis involved increasing the strong ion difference in plasma. Credit was also given for stating the mechanism of action as providing bicarbonate ions to augment the extracellular buffer system
Explain perfusion limited and diffusion limited transfer of gases in the alveolus.
Example answer
Gas diffusion
Rate of diffusion of gasses is given by Fick's Law
<math display="block">Diffusion = \frac {A \times D \; \times \Delta P}{T }</math>
Where: A= lung area, D = diffusion constant of the gas, <math display="inline">\Delta</math>P = partial pressure gradient of gas, T=thickness of membrane. Diffusion constant is influence by the Temperature of the gas, the density of the gas and the size of the molecules
Gas diffusion at the level of the alveolus can either be perfusion or diffusion limited.
Perfusion limited gases
Rapidly equilibrates between alveolus and capillary
Equilibration time is less than the capillary transit time
Thus for the majority of the RBCs time travelling through the capillary, there is no further diffusion
As a result this gas is 'perfusion limited' because increasing the blood flow (perfusion) will increase gas transfer, but increasing the rate of diffusion will not
Examples
Oxygen (under normal conditions)
Due to the large partial pressure gradient (100 > 40)
Equilibrates within 0.25s (pulmonary capillary transit time 0.75s)
Carbon dioxide
While a smaller partial pressure gradient (46 > 40), the diffusivity of CO2 is 20 X greater than O2
Equilibrates within 0.25s
Actually ventilation limited - as you need to blow off CO2 to ensure gradient
Nitrous oxide
Relatively insoluble and doesn't bind to Hb, therefore struggles to equilibrate
Diffusion limited gasses
Does not rapidly equilibrate between alveolus and capillary
Equilibration time is greater than the capillary transit time
Thus for the entirety of the RBCs time in the capillary there is ongoing diffusion occurring
As a result this gas is 'diffusion limited' because increasing the rate of diffusion will increase the rate of gas transfer, but increasing the blood flow (perfusion) will not.
Examples
Carbon monoxide
Slowly diffuses
CO binds to Hb so avidly that there is virtually none in the plasma
Therefore the equilibrium is never reached and further gas exchange could occur with a greater diffusivity
Oxygen
Typically perfusion limited under normal circumstances.
Under extreme conditions it may become diffusion limited
Increase altitude > decreased PAO2
High cardiac output > reduced capillary transit time
Alveolar membrane disease > decreases rate of diffusion
Examiner comments
36% of candidates passed this question.
This question required detail on those factors affecting gas exchange at the level of the alveolus. A description of the components of the Fick equation was expected - and how this related to oxygen and carbon dioxide transfer at the alveolar capillary membrane. The rapid rate of equilibration (developed tension) was the limiting factor in of blood/alveolar exchange that rendered some gases perfusion limited (examples - N2O, O2 under usual conditions but not all) and the slower rate of others diffusion limited (examples CO and O2 under extreme conditions e.g., exercise, altitude). Estimates of time taken for each gas to equilibrate relative to the time taken for the RBC to travel across the interface was also expected for full marks. CO2 despite rapid equilibration and higher solubility was correctly described as perfusion limited (unless in disease states). Better answers described CO2 as ventilation limited. Some answers also correctly included the component of interaction with the RBC and haemoglobin. Ventilation/perfusion inequalities over the whole lung were not asked for and scored no marks
Piperacillin: bactericidal - inhibits cell wall synthesis by preventing cross linking of peptidoglycans by replacing the natural substrate (D-ala-D-ala) with their B-lactam ring
Tazobactam: B lactamase inhibitor (prevents piperacillin degradation)
Renal: AKI
Allergy (up to 10%), rash most common, skin eruptions/SJS and anaphylaxis (<1/10,000)
Pharmacokinetics
Absorption
Minimal oral absorption > IV
Peak concentrations immediately after dose.
Distribution
Very good tissue penetration (minimal CNS without active inflammation)
Low protein binding (<30%)
Metabolism
Piperacillin: not metabolised
Tazobactam: metabolised to M1, an inactive metabolite
Elimination
Renal (80% unchanged)
Special points
Removed by haemodialysis
Examiner comments
62% of candidates passed this question.
Most candidates used a structured approach with the usual major pharmacology headings. Mechanism of action was well described by most, with better answers including mechanisms of resistance. Higher scoring candidates included an explanation as to the combination of the drugs. Likewise, better answers included detailed information on spectrum of activity beyond “gram positive and gram negativeâ€, including relevant groups of organisms which are not covered. There also seemed to be some confusion about coverage for anaerobes, which piperacillin tazobactam covers well. Specific detail about adverse reactions, other than ‘allergy, rash, GI upset, phlebitis, etc’, is expected for commonly used antibiotics.
Describe the principles of measurement of arterial haemoglobin O2 saturation using a pulse oximeter (60% marks). Outline the limitations of this technique (40% marks).
Example answer
Definition
Non invasive spectrophotometric technique to measure O2 saturation in arterial blood
Normal: typically 95-100% (for young health individuals)
Components
Two light sources (LEDs): emit light at 660nm and 940nm
Light detector (photodiode)
Opaque housing unit (minimises ambient light)
Signal amplifier, noise filter
Microprocessor
Connectors , user interface and alarm system
Physical principles
Utilises the principles of the Beer-Lambert law: <math display="inline">A = ε \; l \; c</math>
Absorption (A) of light passing through a substance is directly proportional to
The optical path length (Lambert's law; l)
The concentration of attenuating species within the substance (Beers Law; c)
The absorptivity of the attenuating species ( ε )
Utilises the different absorption spectra of Oxy- and deoxy-Hb
Deoxy-Hb absorbs far more light in the red spectra (660nm)
Oxy-Hb absorbs far more light in the near-infrared spectra (940nm)
How it works
Pulsatile blood (arterial) is isolated and Hb saturation calculated
During pulsatile flow, there is expansion and contraction of the blood vessels
This alters the optical distance (Lamberts law), changing the absorption spectra
Non pulsatile elements (e.g. venous blood) are excluded from the pulsatile elements (arterial blood) by creating a ratio of absorbances (R)
Whereas the ratio of absorbances at different spectra (660nm vs 940nm) utilised to calculate saturation of Hb
The relationship between R and SpO2 was derived empirically by comparing arterial oxygen saturations (from ABGs) at different R values in healthy volunteers
There are important corrections in modern pulse oximeters
Correction for Hb concentration using isosbestic points
Correction for ambient light using rapid cycling of the light source (up to 1000 hz)
Not accurate nor calibrated at low saturations (progressive decline in accuracy as SaO2 decreases)
Not all devices are created equal (device accuracy ranges; generally within 1-5% of ABGs)
Ambient light contamination (effects minimal due to rapid cycling as described above)
Interference: nail polish, oedema, intravascular dyes (methylene blue)
False readings: carbon monoxide poisoning, MetHb
Racial bias in pulse oximetry: tested predominately on white population. A study demonstrated 3x as many black patients had occult hypoxemia compared to white patients.
Examiner comments
74% of candidates passed this question.
Most candidates provided a reasonable structured sequence of how a pulse oximeter generates a value. Nearly all candidates described the Beer-Lambert laws correctly, but few specifically described the basic principles of absorption spectrophotometry. Most candidates had a reasonable list of extrinsic factors that can interfere with pulse oximeter performance, but few described the intrinsic/inherent limitations of the device that can cause SpO2 to be different to SaO2, such as functional versus fractional saturation.
- Essential cofactor in hundreds of enzymatic reactions
- Necessary in several steps of glycolysis (ATP production)
- NMDA receptor antagonism (increasing seizure threshold)
- Inhibits Ach release at NMJ (muscle relaxation)
- Smooth muscle relaxation (Inhibits Ca L-type channels)
Effects
CNS: anticonvulsant (NMDA effect)
Resp: Bronchodilation (CCB effect > SM relaxation)
CVS: Anti-arrhythmic ( decreased conduction velocity due to CCB effect)
Side effects
Related to speed of administration + degree of HyperMg
Urine; clearance is proportional to GFR and plasma concentration
Special points
Incompatible with calcium salts > precipitation
Drug interaction with NMB agents (potentiation)
Examiner comments
57% of candidates passed this question.
The best answers appropriately addressed the pharmacology of magnesium sulphate, rather than diverting into physiology. They noted that the question concerned intravenous magnesium sulphate and did not discuss other routes. They included pharmaceutics, important examples of the wide-ranging indications, listed potential modes of action and considered the full range of body systems affected including potential adverse effects. Drug interactions, such as potentiation of neuromuscular blocking agents, and pharmacokinetics (including stating that magnesium is not metabolised) were described
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
Examiner comments
62% of candidates passed this question.
Good candidates described normal blood flow to the coronary circulation, including differences between the right and left ventricles. Coronary artery anatomy was outlined, including the regions of the heart supplied and the concept of dominance. In addition to epicardial vessels, strong answers also outlined penetrating arteries, subendocardial supply and venous drainage. Regulation of coronary blood flow required an explanation of flow-dependence of the heart given its high oxygen extraction rate. Metabolic autoregulation and its mediators needed to be described, along with the physical factors driving coronary blood flow. Less important mechanisms such as the role of the autonomic nervous system were also described, with an emphasis on indirect effects over direct effects.
19% of candidates passed this question. Overall, this question was poorly answered with a high failure rate. A good answer gave a normal value, iterated that CBF is held relatively constant by autoregulation, and proceeded to divide factors affecting CBF into categories with an explanation/description of each. Those factors with the greatest influence were expected to have more accompanying information (e.g., pressure/myogenic autoregulation, metabolic). Systemic factors such as MAP, O2, CO2 were expected to be mentioned with detail of the impact (i.e., key values, relationships demonstrated with a description and/or labelled graph). Local factors within the brain such as H+ concentration/pH, metabolic activity (including the impact of temperature, inclusion of mediators, regional variation based on activity & grey versus white matter) were also expected to be mentioned. Few answers mentioned impact of pH change independently of CO2. Few answers mentioned how CO2 changes the pH of CSF and that over time, this impact is buffered/reduces. The role of the sympathetic nervous system was required to be mentioned although not explored in detail (although many answers overstated the importance of the SNS on CBF or gave a simplistic concept such as increased SNS activity increases CBF). Many answers focussed on descriptions of the Monro-Kelly doctrine and ICP to the exclusion of the aforementioned factors or included detail on factors influencing MAP which were not required (and irrelevant when within the autoregulation range). Many answers were simplistic: e.g., increase MAP increase CPP therefore increase CBF, or by stating CO2/O2 without mentioning a relationship or the limits/patterns of the relationship. Many answers failed to separate the effect of systemic PaO2 and PaCO2 from metabolic autoregulation.
This question details an aspect of cardiac physiology which is well described in multiple texts. Comprehensive answers included both a detailed description of each action potential and a comparison highlighting and explaining any pertinent differences. The question lends itself to well-drawn, appropriately labelled diagrams and further explanations expressed in a tabular form. Better answers included a comparison table with points of comparison such as the relevant RMP, threshold value, overshoot value, duration, conduction velocity, automaticity, ion movements for each phase (including the direction of movement) providing a useful structure to the table. Incorrect numbering of the phases (0 – 4) and incorrect values for essential information (such as resting membrane potential) detracted from some responses
Define functional residual capacity (10% marks). Outline the functions (70% marks) of the functional residual capacity and the factors affecting it (20% marks).
Example answer
Functional residual capacity
The volume of gas in the lungs at end-expiration during tidal breathing
Typically ~30mls/kg (or ~2.1L in 70kg adult)
Sum of the residual volume and expiratory reserve volume
Represents the point at which the elastic recoil force of lung, and the expanding elastic force of the chest wall are equal
Functions/role of FRC
Oxygen reservoir
Maintains an oxygen reservoir > maintains oxygenation between breaths / periods of apnoea
At FRC, lung compliance is maximal and airway resistance is low
Minimises cardiac workload
At FRC, pulmonary vascular resistance is minimal
Important starting point for measuring lung volumes
Factors effecting FRC
Lung size
Increasing lung size = increasing FRC
Thus affected by
Height (Taller FRC > shorter)
Age (adult FRC > children)
Gender (Male FRC > female)
Respiratory compliance
Increase in compliance
e.g. emphysema, increased PEEP
Leads to increased FRC
Decrease in compliance
E.g. ARDS, obesity, pregnancy
Leads to reduction in FRC
Age (increasing age generally increases FRC)
Anaesthesia
Reduces FRC (multifactorial)
Posture
FRC decreases when going from erect to supine position
Thus if FRC is reduced we will get
Reduction in
Lung compliance
oxygen reserves
tidal volumes
Increase in
airway resistance
pulmonary vascular resistance
atelectasis
work of breathing
V/Q mismatch
Examiner comments
79% of candidates passed this question.
This question was in two parts with the percentage of marks allocated an indication of the relevant time or detail expected per part. The second part of the question also contained two distinct headings which should have been used in the answer. As an outline question, dot points with a brief explanation of each point were expected. Most candidates drew diagrams, few of which added value. For a diagram to add value it should be accurate, have labelled axes, a scale with numerical values and units. As a general rule, diagrams should also be explained and help to illustrate or relate to a written point.
For factors affecting FRC, to score full marks, it should be clearly stated if the factor causes an increase or decrease in FRC. This topic is well covered in the recommended respiratory texts.
Risk of reactivation of latent TB / other infections
Examiner comments
69% of candidates passed this question.
Hydrocortisone is a level 1 drug in the syllabus. Most answers were well structured, many used key headings. In general, detailed information specific to hydrocortisone was lacking. Answers that focused on the mechanism of action, pharmacodynamic effects and pharmacokinetics effects which were detailed and accurate scored well. It was expected that significant detail be included in the sections with relevance to clinical practice for example, the mechanism of action and pharmacodynamic effects including the side effect profile. An indication/appreciation of the timelines of such was also represented in the marking template.
Outline the role of the liver in the metabolism of fat (â…“ marks), carbohydrate (â…“ marks) and proteins (â…“ marks).
Example answer
Carbohydrate metabolism
Glycolysis
Metabolises glucose to generates ATP + pyruvate.
Pyruvate is converted to Acetyl Coa and enters the TCA cycle (aerobic) or is converted to lactate (anaerobic)
Catabolic role
Glycogenesis
The liver can store up to a 100g of glucose in the form of glycogen
Stimulated by insulin (released from the pancreas) when BSLs are HIGH
Anabolic role
Glycogenolysis
Liver can mobilise stored glycogen to produce glucose via glycogenolysis
Stimulated by glucagon (released from pancreas) when BSLs are LOW
Catabolic role
Gluconeogenesis
Liver can synthesise glucose from non-carbohydrate precursors (amino acids, lactate, glycerol)
Stimulated by glucagon (released from pancreas) when BSLs are LOW
Anabolic role
Fat metabolism
Lipid breakdown (B oxidation)
In the liver, free fatty acids undergo B-oxidation to Acetyl CoA
Acetyl Coa then enables energy production by entering Krebs Cycle
Catabolic role
Lipid synthesis
Lipids, including cholesterol, are synthesised in liver from Acetyl CoA
Anabolic role
Lipid processing
Apolipoproteins are synthesised in the liver and are responsible for processing of VLDL, LDL, HDL
Protein metabolism
Protein synthesis
Liver is responsible for synthesis of most plasma proteins (except immunoglobulins)
Anabolic role
Deamination
Individual amino acids have their amino groups removed by liver > a keto acids > TCA cycle
Catabolic role
Amino acid synthesis
Keto-acids can be transformed into non-essential amino acids by transamination, forming new amino acids.
Urea formation
Ammonia (end product of amino acid degradation) is converted to urea > excretion in urine
Examiner comments
54% of candidates passed this question.
This question relates to basic hepatic physiology and is well described in the recommended texts. The mark allocation and division of time was indicated in the question. Better answers used the categorisation in the question as an answer structure. Many candidates gave a good description of beta oxidation, the formation of Acetyl Co A and ketone synthesis. A description of the synthesis of cholesterol, phospholipids, lipoproteins and fatty acid synthesis from proteins and carbohydrates mainly using glycogen, glucose and lactate also received marks. Candidates seem to have a better understanding of fat and glucose metabolism than protein metabolism. Higher scoring candidates appreciated the anabolic and catabolic processes of each component.
Most candidates had a suitable structure to their answers, those without a clear organisation of thought tended to gain fewer marks. In many cases incorrect information or limited detail, particularly around the anatomical organisation prevented higher marks.
Slows/prevents carbohydrate breakdown and absorption
GIT upset
Thiazolidineodiones
Pioglitazone
Increases insulin sensitivity via PPAR receptors in fat cells
Increased risk of heart failure
Meglitinides
Repaglinide
Similar to sulfonureas, though different receptor
Hypoglycaemia, sig. interaction with antifungals > high levels > hypos
GLP-1 agonists
Commonly given S/C
New oral agents are becoming available - not yet widely used in AUS
Examiner comments
37% of candidates passed this question.
High scoring answers most often started with a strong and logical structure and focused on the requested categories of information. Many candidates gave good answers across the wide range of drugs. Several candidates could have scored more highly by giving more correct information on biguanides and sulphonylureas.
Decreased risk of trauma, infection, haemorrhage. Not therapeutic. Cannot be recalibrated and prone to drift. More expensive. measures local ICP only
Examiner comments
22% of candidates passed this question.
This question is ideally suited to a tabular format, where candidates are expected to highlight the significant similarities and differences as well as why a certain monitor may be chosen in preference to another rather than compile two lists written next to each other. To score well in this question, a statement of what could be measured (ICP: global vs local), a description of the measurement principles, along with other measurement related information like calibration and sources of error was required. Also sought was information regarding anatomical placement (e.g., lateral ventricle for EVD) and method of placement.
Furthermore, a comparison with each other (e.g., higher infection/bleeding risk with EVD, greater risk of trauma due to size and insertion, expertise to insert, cost, therapeutic benefit, risk of blocking) was required for completion. Candidates who structured these elements into advantages and disadvantages were generally able to elucidate this information and score better.
Can voluntarily cough, however the cough reflex = involuntary
Purpose of cough reflex
Airway protective function
Helps clear foreign material/noxious stimuli from the airway
N.B: Useful clinically in brain death testing
COUGH REFLEX
Sensors
Rapidly adapting mechanoreceptors, slowly adapting mechanoreceptors, and c-fibres
Stimulus for cough
Chemical, mechanical, noxious stimuli in the airways (larynx, trachea, carina, bronchi)
e.g. leukotrienes, histamine, bradykinin, foreign bodies
Afferents
Afferents from the internal laryngeal nerve (br. of vagus nerve)
Integrator/controller
Vagal afferents synapse in the medullary respiratory centre (NTS)
Efferents
Diaphragm (via phrenic nerve)
Abdominal muscles (via spinal motor nerves)
Larynx (via laryngeal branch of vagus nerve)
Effector / mechanism
Coordinated action of respiratory, pharyngeal, abdominal muscles
Phase 1: inspiratory phase
Deep inspiration to near vital capacity (muscles of inspiration, including diaphragm)
Phase 2: compressive phase
Closure of the cords+epiglottis, contraction of the abdominal and intercostal muscles
Leads to dramatic rise in intrapleural pressure (>100cmH2O)
Phase 3: expulsive phase
Sudden partial opening of the cords and epiglottis
Leads to violent expiration of turbulent air removing foreign material
Examiner comments
62% of candidates passed this question.
Overall, this question was reasonably well answered. Those that performed well had suitably detailed knowledge and structured their responses which generally included a definition and purpose of the reflex as well as the identification and a description of the afferent, integrator/controller, and efferent limbs of the reflex. This structure allowed a logical platform for the elucidation of the detail required in the answer, including types of stimulus, receptors, nerves (for both limbs of the reflex) and the muscles used in the phasic response to be clearly articulated.
Not readily stored - readily excreted in urine > less likely to be toxic
Trace elements
E.g. zinc, copper, iron, selenium, iodine
Needed for daily functioning in trace amounts
Examiner comments
40% of candidates passed this question.
This topic is well covered in the recommended physiology textbooks. Many answers unfortunately simply listed the various components without providing sufficient detail; outline questions require some context around the key points as opposed to just a list.
Most candidates had a good estimate for the basal energy requirements of a resting adult. Good candidates were able to outline the g/kg daily protein requirements and the distribution of remaining energy intake between carbohydrates and lipids and included how this may change during periods of stress. They also stated the energy derived per gram of each of those food groups. Few candidates mentioned the need to include essential amino acids. Similarly, with fat intake, few candidates mentioned the need for essential fatty acids. A definition of “vitamin†would have received credit. Most candidates were able to classify vitamins as water soluble or fat soluble. Most candidates mentioned trace elements (with an abbreviated list) and mentioned bone minerals. A daily intake requirement for Na and K was expected, though not for bone minerals or trace elements.
Facilitate endotracheal intubation during anaesthesia (i.e. RSI)
Pharmaceutics
Clear colourless solution (50mg/ml), needs refrigeration (4°C) or else lasts only a couple of weeks at room temp
Routes of administration
IV, IM
Dose
1-2 mg/kg (IV), 2-3 mg/kg (IM)
Pharmacodynamics
MOA
Binds to the nACh receptor on motor end plate > depolarisation. Cannot be hydrolyed by Acetylcholinesterase in NMJ > sustained depolarisation (i.e. Na channels remain in open-inactive state) > muscle relaxation
Rapid hydrolysis by plasma cholinesterase's (~20% reaches NMJ)
Elimination
Minimal renal elimination (due to rapid metabolism)
Special points
May have prolonged duration of action with congenital or acquired (e.g. liver, renal, thyroid disease) pseudocholinesterase deficiency
Treatment of malignant hyperthermia is with dantrolene (+ cooling + supportive care)
Examiner comments
63% of candidates passed this question.
This was a level 1 pharmacology question, and it represents core knowledge. The mechanism of action of suxamethonium and the interactions at the neuromuscular junction as well as pharmaceutics were areas that often required further detail. Few candidates mentioned the effects of suxamethonium on the autonomic nervous system. Another common omission related to the factors that reduce plasma cholinesterase activity beyond genetic deficiency (such as liver disease, renal failure, thyrotoxicosis). Pleasingly, there was generally a good understanding of role, dosing, side effect profile, pharmacokinetics and of special situations and limitations of use pertinent to this drug.
Various other questions relating to properties of NMB more broadly
Question 11
Question
Describe the changes in the circulatory system that occur during exercise.
Example answer
Exercise
Leads to increased oxygen demand (predominately skeletal muscle) and increased metabolic waste products which need to be cleared
Leads to many circulatory changes:
Cardiac output
Increased oxygen demand > increased CO (as CO is the main modifiable component of the oxygen delivery equation - Hb, Sats, PaO2 not readily changeable)
Most of the increased CO goes to skeletal muscle beds
With increasing HR, SV will begin to decrease (due to reduced diastolic filling time)
Plateaus at ~50% VO2max
Redistribution of blood flow
Vasodilation in skeletal muscle beds
Mediated by local factors (hypoxia, CO2, Lactate, adenosine) which lead to vasodilation (to decrease resistance, thus increase blood flow)
Also mediated by autonomic factors: SNS activation > B2 stimulation > vasodilation
Vasoconstriction of non working tissues
SNS mediated vasoconstriction of GIT, Kidneys > blood flow directed to "working tissues"
Coronary blood flow
Increases by metabolic autoregulation due to increased demand from increased inotropy/chronotropy
Cerebral blood flow
Remains constant (autoregulation) - no increase in metabolic demand. Increased BP > myogenic vasoconstriction.
Increased oxygen extraction
Increased CO2 and H+ and temperature in working skeletal muscle beds > right shift of the oxygen-Hb dissociation curve > increased O2 extraction (Bohr effect)
Blood pressure/s
Increased SBP (due to increased inotropy > increased CO)
Decreased DBP (due to reduced SVR from skeletal vasodilation)
Overall increase in MAP (increase in CO is greater than reduction in PVR)
Other haemodynamics
Increased venous return > increased CVP and PCWP
Examiner comments
22% of candidates passed this question.
This is an applied physiology question. Better answers categorised the changes in some manner and included a measure of the degree of change as applicable (e.g., what increases, what decreases and what may stay the same). The question was to describe the changes so that the detail behind the mechanisms enabling these changes to occur was expected (e.g., neurohumoral, local factors). Marks were also awarded for any regional variation that occurs
Related to volume of fluid (i.e. volume expansion) and role of albumin (oncotic, transport, etc)
Side effects
No risk of bacteria/parasite infections (destroyed during processing), but risk of blood borne viruses (HIV, HepB, HCV) remains.
Allergy, fluid overload.
Pharmacokinetics
Absorption
IV only (0% oral bioavailability)
Distribution
Rapid distribution within intravascular space.
Small Vd - about 5% leaves per hour
Metabolism
Cellular proteolysis by cysteine protease
Elimination
Degradation by liver and reticuloendothelial system
Special points
- May worsen outcomes in TBI
- No need for blood cross matching
Examiner comments
19% of candidates passed this question.
The question required an equal treatment of the physiology and pharmacology of albumin. The physiology discussion needed to include synthesis, factors affecting synthesis, distribution in the body (including the proportion divided between the plasma and interstitial space), functions, breakdown, and elimination half-life. Discussion of the pharmacology should have included available preparations (4% and 20% Albumin) and pharmaceutics, distribution, elimination (both the protein and crystalloid components), mechanism of action to expand the plasma compartment, longevity in the plasma compartment, indications, and adverse effects. Oedema, circulatory overload, immunological reactions, and relative contraindication in brain injury were important to mention. There was some confusion regarding the infectious risks of albumin. An outline of the manufacturing process from donated plasma and pasteurisation was expected.
Arteries and veins travel with respective bronchi, nerves and lymphatics in bronchovascular bundle
Physiological features (pulmonary circulation)
Low pressure system
Normal PA
Systolic pressure 15-25mmHg
Diastolic pressure 8-15mmHg
Mean pressure 10-15mmHg
Pulmonary venous pressure ~8-10mmHg
Low resistance system
~100-200dynes/sec/cm-5
~10% of systemic circulation
With further flow (e.g. increased CO during exercise) can maintain low resistance by recruitment of additional capillaries
High flow system
Pulmonary arterial flow = cardiac output
Needs capacity to expand (highly elastic) with increasing CO
Volume
Contains ~10% circulating blood volume (~500mls)
Has capacity to expand (highly elastic, recruit additional capillaries)
Regional distribution of blood flow
Right lung receives 55% CO, left lung 45% CO
Flow distributed according to hydrostatic and alveolar pressure (west zones)
Hypoxic pulmonary vasoconstriction can redirect blood flow away from poorly ventilated regions
Regulation
Minimal capacity to self regulate (except for hypoxic vasoconstriction) with weak autonomic activity
Response to hypoxia: vasoconstriction
Response to hypercapnia: vasoconstriction
Functions
Main function is gas exchange: Absorbs O2, releases Co2
Other functions: filtration clots/debris, source of ACE, metabolism of PGs
Examiner comments
25% of candidates passed this question.
The examiners consider that an understanding of the pulmonary circulation is core area of the syllabus. In general, the anatomy section was better answered than the physiological features. As well as a description of the gross anatomy of the pulmonary circulation tracking it from the pulmonary valve to the left atrium, some mention of the microscopic anatomy was required (e.g., that the pulmonary arteries are thin walled with little smooth muscle).
For the second part of the question, a breadth of knowledge was required. Candidates were expected to address the following physiological features of the pulmonary circulation: volume, pressure, resistance, regulation and regional distribution and function. Marks were apportioned to each section, so it was important to write something on each section. Focussing on one section in detail (e.g., a very detailed description of West’s Zones) usually came at the expense of missing one or more of the other sections, most commonly the functions of the pulmonary circulation. Indeed, candidates that scored well provided information on each section and for the functions of the pulmonary circulation mentioned more than gas exchange.
Motor: All laryngeal muscles are supplied by the RLN except the cricothyroid which is supplied by the External branch of the superior laryngeal nerve
Sensory: internal branch of the superior laryngeal nerve (above cords), RLN (below cords)
Arterial supply
Upper half: Superior laryngeal artery (br. from the superior thyroid artery)
Lower half: Inferior laryngeal artery (br. of the inferior thyroid artery)
Venous drainage
Superior and inferior laryngeal veins which drain into respective thyroid veins
Lymphatics
Above the vocal cords: superior deep cervical LNs
Below the vocal cords: inferior deep cervical LNs
Examiner comments
40% of candidates passed this question.
For this question, candidates were expected to address the location of the larynx, its relations, the cartilages (single and paired), ligaments, muscles (intrinsic and extrinsic), innervation (sensory and muscular) and blood supply (including venous drainage). Marks were apportioned to each section, so whilst some detail was required, breadth of knowledge was also important. Most candidates had a grasp of the gross anatomy, the main relations and at least the innervation provided by the recurrent laryngeal nerve. However, an understanding of the functional anatomy of the cartilages was not always apparent. It should be noted that not every single muscle needed to be named (especially for the extrinsic muscles), but an understanding of the major muscle groups should have been included
By liver into inactive metabolites (95%) and active metabolites (5%)
Elimination
Renal (70%) and faecal (20%) excretion of metabolites
T 1/2 = 2mins
Renal elimination of metabolites (active metabolites last as long as 80 hours)
Special points
Does not require SAS approval
Requires SAS approval in AUS
Examiner comments
41% of candidates passed this question.
The objective of this question was that candidates relay a detailed knowledge of both drugs with respect to their individual pharmacology highlighting the important clinical aspects of each drug (e.g., mechanism of action, metabolism, duration of effect). Then an integration of this knowledge was in the contrast section where the better candidates highlighted features of the drug that would influence when or why one may use it with respect to the second agent. Tabular answers of the pharmacology of each drug without any integration or comparison scored less well. A detailed knowledge of both agents was expected to score well.
Describe the formation of gastric acid (50% marks) and the regulation of gastric acid secretion (50% marks).
Example answer
Gastric acid
Gastric acid (HCl, pH 1.6) is one component of gastric secretions
Other components include: Gastrin, pepsinogen, IF, mucous
~2L of gastric secretions produced per day
Gastric acid is important for innate immunity, pepsin activity, iron absorption etc.
Formation of gastric acid
Produced by the parietal cells in the stomach
Mechanism of HCl production
CO2 diffuses into parietal cells from blood
CO2 reacts with water to give H2CO3 (catalysed by CA)
H2CO3 dissociates into H+ and HCO3
At the basolateral membrane: HCO3 is exchanged for Cl (Cl in, HCO3 out)
Cl then passively diffuses down concentration gradient into secretory canaliculi
At the apical membrane: H-K ATPase pumps H+ into secretory canaliculi (against concentration gradient)
Stages of secretion
Cephalic
~30% of gastric secretions as a result of this phase
Due to thought / taste / sight / smell of food
Leads to increased PSNS (vagal) activity
Gastric
~60% of gastric secretions during this phase
Due to the mechanical stretch of the stomach by the food
Leads to increased PSNS activity and gastrin release
Intestinal
<10% of gastric secretions during this phase
Distention of small intestine --> release of secretin
Increased acid load in duodenum --> release of somatosatin
Regulation of gastric acid secretion
Histamine
Most important stimulus for gastric acid secretion
Synthesised and stored in neighbouring ECL cells
Binds to H2 receptors on parietal calls > HCl release
Stimuli: PSNS activity + gastrin
PSNS (vagal) activity
Vagal nerve stimulation of M3 receptors (Ach) on parietal cells > increased release HCl
Vagal stimulation of ECL cells > increased release histamine
Gastrin
Released from G cells
Indirectly leads to increased release of histamine from ECL cells
Activated by vagus, Inhibited by secretin
Somatostatin
Released from D cells
Inhibits gastrin
Secretin
Released from S cells
Inhibits gastrin
Examiner comments
26% of candidates passed this question.
The is question was divided into two sections offering equal marks. The first section required a description of the generation and transport of both H+ and Cl- into the stomach lumen by the parietal cell. The contributions of basolateral and luminal ion channels, the role of carbonic anhydrase and accurate description of the net flux was expected for full marks. The second section required comments on the roles of neural and endocrine regulation. Increased acid secretion via acetylcholine (via muscarinic M3), histamine (via H2) and gastrin were expected as was reduced secretion via secretin and somatostatin. Better responses were able to combine and integrate these into cephalic, gastric, and intestinal phases. The nature and function of other gastric secretions and the role of pharmacologic agents was not asked for and therefore not awarded any marks.
hypotension
Rebound pHTN following abrupt cessation
Thrombocytopaenia
Pharmacokinetics
Onset
Seconds
Absorption
Rapidly absorbed in pulmonary circulation due to high lipid solubility
Distribution
Minimal systemic distribution
Metabolism
Reacts with oxyHb to produce methaemaglobin and nitrates.
T 1/2 5 seconds
Elimination
Metabolites (main metabolite = nitrate) are renally excreted
Special points
Examiner comments
24% of candidates passed this question.
Nitric Oxide (NO) is an inorganic colourless and odourless gas presented in cylinders containing 100/800 ppm of NO and nitrogen. Many candidates mentioned oxygen instead of nitrogen. The exposure of NO to oxygen is minimized to reduce formation of nitrogen dioxide and free radicals. Hence it is administered in inspiratory limb close to the endotracheal tube. Many candidates did not mention the contraindications/caution for NO use. Candidates generally did well in mentioning the impact on improving V/Q mismatch by promoting vasodilatation only in the ventilated alveoli and reducing RV afterload. Many candidates did not mention the extra cardio-respiratory effects. The expected adverse effects of NO were nitrogen dioxide related pulmonary toxicity, methemoglobinemia and rebound pulmonary hypertension on abrupt cessation. Pharmacokinetics of NO carried a significant proportion of marks. It was expected that the answers would involve mention of location of delivery of NO in inspiratory limb and reason behind it, the high lipid solubility and diffusion, the dose (5-20ppm), very short half-life of < 5 seconds and combination with oxyhemoglobin to produce methaemoglobin and nitrate. The main metabolite is nitrate which is excreted in urine.
Vessel radius (most important factor, changes readily)
E.g. profound vasoconstriction of capacitance vessels (e.g. norad infusion) > increased resistance > increased afterload
Outflow tract impedance
Leads to increased afterload (increased forced required for ejection)
E.g. valvular disease (AS), SAM, LVOT
Examiner comments
53% of candidates passed this question.
Afterload can be defined as factors resisting ventricular ejection and contributing to myocardial wall stress during systole. Most answers utilised the law of Laplace to expand upon factors affecting ventricular wall tension. Systemic vascular resistance was commonly mentioned, but less frequently defined. Aortic and left ventricular outflow tract impedance were commonly referred to. Effects of preload and neurohumoral stimuli were less well outlined. Description of factors affecting right ventricular afterload and depictions of left ventricular pressure volume loops earned no extra marks unless directly referenced to the question.
Normal biproducts of cellular function and metabolism
'Fixed acids'
Body produces ~1mmol/kg/day
Fixed acids, except for lactate, are eliminated by the kidneys
'volatie acids' (i.e. CO2)
Body produces ~15-20moles/day
Eliminated by the lungs
Mechanisms of acid-base regulation by kidneys
Secretion of H+ / Reabsorption of HCO3
H+ activately secreted into the urine
Na-H exchanger (PCT, LOH)
H+ ATPase (DCT)
H-K ATPase (CD)
HCO3 is freely filtered at glomerulus (needs to be reabsorbed)
H+ and HCO3 combine to form H2CO3
H2CO3 converted to H2O and CO2 (by apical carbonic anhydrase)
H2O aand CO2 diffuse into cell and converted back to H2CO3 by CA
H2CO3 then dissociates into HCO3 and H+ (HCO3 reabsorbed, H+ is secreted once more)
This allows for all HCO3 to be reabsorbed
Combination with titratable acids
Excess H+ combines with filtered buffers (e.g. phosphate, sulphate)
Phosphate is most important and is responsible for eliminating ~40% of excess fixed acid load / day
H+ combines with HPO4 > H2PO4 (ionised, not reabsorbed)
Minimal capacity to increase
Ammonium mechanism
Excess H+ can bind to ammonia > excreted
in PCT/DCT: metabolism of glutamine > releases new HCO3 and excess NH4
In CD: secretion of NH3 binds to H+ > NH4 (ionised and cannot be reabsorbed)
Accounts for remainder of excess fixed acid load,
Has capacity to greatly expand when there is excess H+
Examiner comments
51% of candidates passed this question.
This question required candidates to understand the renal response to an acid load. It was expected that candidates would answer with regard to recycling of bicarbonate in the proximal tubule, excretion of titratable acid via the phosphate buffer system and generation of ammonium and its role in acid secretion. Many candidates had a good understanding of the bicarbonate system but used this to explain the secretion of new acid.
This was a straightforward pharmacology question relating to a relatively common and archetypal intensive care medication. The structure of the question was well handled by most of the candidates; easily falling into the classic pharmaceutics, pharmacokinetic and pharmacodynamics framework. Many candidates had a superficial knowledge of the presentation and formulation of the drug, aside from its light sensitivity. Better answers detailed the drug according to the above-mentioned framework but also accurately highlighted specific points relevant to the ICU practise such as the metabolic handling of sodium nitroprusside and relating this to the consequences of the various metabolic products.
CO2 dissolves into RBC and leads to H+ and HCO3 (per above equation)
HCO3 moves into plasma, H+ binds to reduced (deoxy) Hb
KHb + H+ <-> HHb + K+
Cl moves into the cell to maintain electroneutrality (chloride shift)
When Hb is oxygenated in the lungs, H+ dissociates and converted back to CO2 by the above equation and is exhaled
Haldane effect accounts for the increased capacity of Hb to carry CO2 when poorly oxygenated
Carbamino compounds
Accounts for
~5% of the CO2 in the blood
~30% of the CO2 evolved by the lung
Formed by the combination of CO2 with terminal amine groups in blood proteins
NH2 + CO2 <-> NHCOO- + H+
Haemoglobin is the most abundant protein and has most imadazole side chains (greatest carrier capacity)
The reaction occurs faster with deoxHb than oxy-Hb (Haldane effect)
Examiner comments
68% of candidates passed this question.
A detailed understanding of the carriage of carbon dioxide (CO2) in the blood is essential to the
practice of intensive care medicine. Comprehensive answers classified and quantified the
mechanisms of CO2 carriage in the blood and highlighted the differences between the arterial and
venous systems. An explanation of the physiological principles surrounding these differences and
the factors which may affect them was expected. The changes that occur at the alveolar and
peripheral tissue interfaces with a similar explanation of process was also required. Candidate
answers were often at the depth of knowledge required for an ‘outline question’ and a more
detailed explanation was required to score well.
Patch: 5/15mg/24hr SL: 400mcg PRN IV: titrated to effect
pKA
5.6
Pharmacodynamics
MOA
Prodrug, which is dinitrated to produce active nitric oxide (NO). NO diffuses into smooth muscle cell > binds to guanylyl cyclase > increased cGMP > decreased intracellular Ca > smooth muscle relaxation > vasodilation
Can develop tachyphylaxis (depletion of sulfhydryl groups)
Examiner comments
69% of candidates passed this question.
GTN is a commonly used ‘level 1’ drug. The most comprehensive answers included information
on available drug preparations, indications, mechanism of action, pharmacodynamics and
pharmacokinetics and its side-effect profile. It was expected that significant detail be included in
the pharmacodynamic section (e.g. preferential venodilation, reflex tachycardia, effects on
myocardial oxygen demand etc). Common omissions included tachyphylaxis, dosing and its
metabolism. Many answers didn’t mention the first pass effect.
Alloimmunized to minor RBC antigens (kidd, duffy, Kell) during previous transfusions which is not detected due to low levels in pre-transfusion screening. Reaction if re-exposed
Transfusion associated graft versus host disease
Rare
Transfused lymphocytes recognise host HLA as positive causing marrow aplasia (rare now with leukodepletion)
Alloimmunisation
~1-10%
Previous sensitisation leading to antibody production on re-exposure.
Non-immunological (acute < 24 hours)
Adverse event
Incidence
Mechanism
Non immune mediated haemolysis
Rare
Due to physicochemical damage to RBCs
Transfusion transmitted bacterial infections
1:250,000 - 2.5 million
Contamination during collection or processing. Most common organisms are those which use iron as a nutrient and reproduce at low temperatures, e.g. Yersinia Pestis.
Transfusion associated circulatory overload
1%
Rapid increase in intravascular volume in patients with poor circulatory compliance or chronic anaemia. May result in pulmonary oedema and be confused with TRALI.
Each unit of PRBC contains ~250mg of iron, whilst average excretion is 1mg.day-1.
Infections
Less than 1:1 million
From donor
Examiner comments
43% of candidates passed this question.
As only an outline was asked for, a brief statement about each complication was sufficient. Better answers were structured using a classification of: Acute Immunological, Acute Non- Immunological, Delayed Immunological and Delayed Non-immunological. Examples of expected detail would include the following: E.g. Bacterial infection – a statement outlining the incidence of bacterial infection, a common causative organism or why bacterial infections are more commonly associated with platelet transfusions than red cells would have scored the marks allocated to ‘bacterial infection’. E.g. Acute Haemolytic Transfusion Reaction – a statement about red cells being destroyed due to incompatibility of antigen on transfused cells with antibody of the recipient and an approximate incidence scored the marks allocated to AHTR. An excellent resource is the Australian Red Cross transfusion website as listed in the suggested reading section of the syllabus.
Explain the counter-current mechanism in the kidney.
Example answer
Purpose
The counter current mechanism of the kidney is important for establishing the osmotic gradient necessary for forming concentrated urine (thus preserving water)
Formation
Formed by the loop of henle
Assuming a naïve system. Iso-osmolar fluid (300mosm) arrives at the aLOH.
This is because water/solutes are absorbed in equal amounts in the PCT.
In the aLOH the Na-K-2Cl transporter reabsorbs these ions. Water is impermeable. Interstitium becomes hyperosmotic (now 400mosm)
When the next iso-osmotic fluid arrives (300sm), there is a concentration gradient (water leaves through permeable dLOH) leading to hypertonic filtrate
The hypertonic filtrate then arrives in the aLOH and the Na-K-2Cl pump works again.
The interititum becomes further hypertonic (e.g. 400mosm).
Process repeats until a maximal concentration gradient of around 600mosm exists between inner medulla and cortex
Finally, through urea trapping from the collecting ducts (facilitated diffusion via UTA1 and UTA3 receptors), the osmotic gradient in the inner medulla is increased to approximately 1200mosm
Maintenance
Vasa recta is organised in such a way that it does not wash away the established concentration gradient (close proximity, in parallel, opposite direction of flow)
Achieves this by also looping down into the inner medulla (water lost, solute gained) then back up (water gained, solute lost)
The slow nature of this flow in combination with its anatomy (parallel + close proximity) prevents the washing away of the concentration gradient
This is known as the counter current exchanger
Examiner comments
63% of candidates passed this question.
Higher scoring candidates described the counter-current multiplier mechanism, the countercurrent
exchanger and the contribution of urea cycling to the medullary osmotic gradient. Detailing
the mechanisms as to how they may be established, maintained and or regulated. Descriptions
of the multiplier (LOH) alone did not constitute a passing score. Values for osmolality at the cortex
& medulla and within the different parts of the LOH was required. A description of the countercurrent
exchanger system where inflow runs parallel to, counter to and in close proximity to the
outflow was expected. This could have been achieved by describing the anatomical layout of the
loop of Henle and the vasa recta.
Vd 2.5L/kg. Protein binding 25%, good tissue penetration (except for poor CSF penetration)
Metabolism
Partially hepatic
Elimination
Renal excretion of metabolites. T1/2 3-5 hours.
Special points
Increasing world wide resistance to quinolones.
Examiner comments
71% of candidates passed this question.
Most candidates had a structured answer to mechanisms of resistance that covered the major categories (alter target protein, prevent entry, efflux, degrade drug) and provided an example of a bacteria and the affected antibiotic, as was required to answer the question in full. Ciprofloxacin, whilst perhaps not a first line drug in the ICU, was not well known by many candidates. Better answers included a brief outline of class, mechanism of action (action on DNA gyrase to inhibit replication), spectrum (Gram negatives particularly mentioning Pseudomonas, lesser Gram positive cover, not anaerobes, some atypical), PK (with correct dose, wide penetration into tissues including bone/prostate etc., predominantly renal excretion), side effects/toxicity (common or specific to cipro e.g. QT, tendinitis, arthropathy) and an example of resistance.
Immature respiratory centre - decreased response to hypercapnia, periodic apnoea,
Examiner comments
20% of candidates passed this question.
This question required an outline of the anatomical, mechanical and functional differences. It was expected that factors leading to an increased work of breathing and oxygen cost would be mentioned. The mechanics of expiration were not often included in candidates’ answers. Immaturity of the alveoli and peripheral chemoreceptors were common omissions. Inaccuracies regarding upper airway anatomy and compliance of the chest wall cost some candidates marks. The question did not call for an explanation of the relative difficulty of intubation. Discussion of pathophysiology due to airway obstruction, causes of central apnoea or sensitivity to drugs was not required. Many answers included inaccurate information. Points which were often missed were difference in bronchial angles, number of alveoli, number of type 1 fibres in diaphragm, ciliary function and peripheral chemoreceptors.
Describe the physiological control of systemic vascular resistance (SVR).
Example answer
Overview
SVR is the impediment to flow generated by the systemic vasculature (excluding pulmonary) and can be defined according to ohms law (SVR = (MAP-CVP) / CO)
The main determinants of SVR is conceptualised by the Hagen-Poiseuille equation
Length (l), and viscosity of blood (n) does not readily change, hence the most significant determinant of SVR is the vessel radius (R)
Control of radius
Majority of this control occurs at the level of the arteriole (sig. amount of smooth muscle in wall - can readily alter calibre)
Systemic control of vessel radius
SNS
Activation of the SNS (pain, emotion, exercise, fear etc) > release of NA from the post ganglionic neurons > activates alpha-1 receptors > vasoconstriction > increased SVR
Alpha-1 receptors are plentiful in the skin, kidneys, GIT (but minimal in the heart and brain, leading to preferential flow to these organs)
PSNS
Much less important (external genitalia)
Activation leads to vasodilation (decreased SVR)
Arterial baroreflex control
Increased BP > increased arterial wall stretch > increased firing of aortic and carotid sinus baroreceptors > decreased sympathetic tone > vasodilation > decreased SVR (vice versa)
Chemoreceptor reflex
Peripheral and central chemoreceptors activated by hypoxia > increased SVR
Hormonal control
Numerous endocrine mediators affect SVR
E.g. Angiotensin (AT1 receptors) and vasopressin (V1 receptors) increase SVR
This question invited a detailed discussion of the physiological control mechanisms in health, not
pathophysiology nor drug-mediated effects. The central and reflex control mechanisms that regulate SVR over time are distinct from the local determinants of SVR. There was often confusion between dependent and independent variables. Cardiac output is generally depended upon SVR, not vice versa, even though SVR can be mathematically calculated from CO and driving pressures. The question asked about systemic vascular resistance and did not require a discussion of individual organs except for a general understanding that local autoregulation versus central neurogenic control predominates in different tissues. Emotional state, temperature, pain and pulmonary reflexes were frequently omitted. Peripheral and central chemoreceptors and low-pressure baroreceptors were relevant to include along with high pressure baroreceptors.
Describe the production, metabolism and role of lactate.
Example answer
Production
Lactate is a product of anaerobic metabolism
Glucose is converted to pyruvate via glycolysis
Aerobic metabolism: Pyruvate is converted to Acetyl Coa and enters the TCA cycle > oxidative phosphorylation (38 ATP per glucose)
Anaerobic metabolism: pyruvate is unable to be converted to Acetyl CoA and enter the TCA cycle. Instead it is converted into lactate (producing 2 ATP and regenerates NAD+ to allow glycolysis to continue)
Lactate is produced mainly in skin, muscle, RBCs, brain, intestines
Normal plasma levels are ~0.5-2mmols
Increased lactate (>2 mmols) may be due to numerous causes
Physiological causes: E.g. exercise
Hypoxaemia: e.g. Shock, anaemia, CO poisoning, hypoxia
Disease: e.g. Sepsis, liver failure, thiamine def.
Drugs/toxins: e.g. adrenaline, salbutamol, ethanol, biguanides, cyanide
Congenital errors in metabolism: e.g. G6PD deficiency
Metabolism/fate
Lactate produced intracellulary diffuses out of the cell
Majority (80%) of circulating lactate is then metabolised in the liver via the cori-cycle
Lactate is converted back to glucose via gluconeogenesis (consumes 6ATP), and can undergo glycolysis again
Lactate can also be used as a fuel source, for example in the heart
Role
Lactate sink
Allows a period of ongoing ATP production from glycolysis during periods of hypoxia, TCA inhibition, pyruvate accumulation
Lactate shuttle hypothesis
Lactate is produced under aerobic+anaerobic conditions and may shuttle intra-cellularly and inter-cellularly to be used as sources of energy via gluconeogenesis
Signalling molecule
Emerging evidence that lactate
alters gene expression
may be involved in redox signalling
Mediate control of lipolysis
Examiner comments
16% of candidates passed this question.
Better answers used the categorisation in the question as a structure for their answer. Many candidates gave a good description of lactate production from glycolysis, increasing with accumulation of NADH and pyruvate, when these are unable to enter Krebs cycle. There were however, many vague and incorrect descriptions as to what lactate is and its physiological role. Many candidates suggested that its presence is abnormal or pathological. Most answers demonstrated a superficial understanding and physiological detail of lactate’s role as an energy currency in times of oxygen debt. Higher scoring candidates often mentioned non-hypoxic causes of pyruvate accumulation which include; circulating catecholamines, exercise, sepsis or lack or mitochondria (RBCs). Mention of the relative ATP production of the two fates of pyruvate was also noted in more complete answers. The Cori cycle was generally superficially described. A key role of lactate is the ‘lactate sink’, allowing a period of ongoing ATP production from glycolysis when cells become oxygen deplete or the Kreb’s cycle is inhibited; few candidates detailed or highlighted this.
Outline the changes to drug pharmacokinetics and pharmacodynamics that occur at term in pregnancy.
Example answer
Pharmakokinetics
Absorption
Oral
Nausea and vomiting in early preg > reduced PO absorption
Increased intestinal blood flow (due to increased CO) > increased PO absorption
Decreased gastric acid production > increased pH > unionised drugs absorbed more
Delayed gastric emptying peri-labour may increase/decrease absorption depending on drug
IM / SC / Transdermal
Increased absorption due to increased CO + increased skin/muscle blood flow
IV
Faster IV onset due to increased CO
Neuraxial
Decreased peridural space > decreased dose required
Distribution
Volume of distribution
Increased total body water > increased Vd for hydrophilic drugs
Increased body fat > increased Vd for lipophilic drugs
Plasma proteins
Decreased protein binding (increased free fraction) due to reduced concentrations albumin and a-1 glycoprotein
Metabolism
Liver
Some metabolic enzymes reduced / some increased (due to progesterone/oestrogen ratio)
Leads to variable drug responses
E.g. increased metabolism of midazolam, phenytoin, but decreased caffeine.
Placenta metabolises some drugs (?sig of effect)
Decreased plasma cholinesterase (though no change in Succinylcholine effect)
Elimination
Renal
Increased clearance due to increased GFR (e.g. cefazolin)
Hepatobiliary
Decreased clearance due to cholestatic effects of oestrogen (e.g. rifampacin)
Resp
Increased volatile washout due to increased minute ventilation
Pharmacodynamics
Increased sensitivity to volatile anaesthetics (decreased MAC)
Increased sensitivity to IV anaesthetics
Increased sensitivity to local anaesthetics
Changed therapeutic indices due to risk of teratogenicity / fetal damage
Examiner comments
7% of candidates passed this question.
Answers framed around absorption, distribution, metabolism and excretion performed better. Some brief comments on physiology are required as the basis for pharmacokinetic change, but discussion of physiology that was not then specifically related to pharmacology did not score marks. Specific ‘real life’ examples necessitating change in practice or prescribing were well regarded e.g. reduction in spinal/epidural local anaesthetic dosing. Vague statements about possible or theoretical changes were less well regarded.
HAEM: Excessive platelet aggregation / thrombosis
RENAL: Hyponatraemia (increased water reabsorption > Na reabsorption)
GIT: abdominal pain , nausea, vomiting
DERM: Ischaemia from vasoconstriction
Allergic reactions (bronchospasm, urticarial rash, anaphylaxis)
Pharmacokinetics
Onset
Immediate
Fast (not as fast as noradrenaline)
Absorption
IV only (0% oral bioavailability)
IV only (0% oral bioavailability)
Distribution
Does not cross BBB.
Vd = 0.1L/kg
Protein binding = 25%
20% protein bound, Vd 0.2L/Kg
Metabolism
Readily metabolised by MAO and COMT into inactive metabolites (VMA, normetadrenaline). 25% taken up in lungs.
Extensive hepatic and renal metabolism by serine proteases and oxido-reductase enzymes > inactive metabolites
Elimination
Excreted in urine as inactive metabolites (>85%).
Half life ~2 mins
Renal elimination
T 1/2 <10 minutes
Special points
Tachyphylaxis (slow)
Effect exaggerated in patients taking MAOI (less breakdown)
Examiner comments
49% of candidates passed this question.
These are both level 1 drugs regularly used in intensive care. Significant depth and detail of each
drug were expected. Overall knowledge was deemed to be superficial and lacked integration.
Better answers identified key points of difference and overlap in areas such as structure, pharmaceutics, pharmacokinetics, pharmacodynamics, mechanism of action, adverse effects
and contraindications. A tabular list of individual drug pharmacological properties alongside each
other did not score as well as answers which highlighted key areas of difference and similarities.
None directly comparing these. Some a while back on norad or vaso individually
Question 11
Question
Describe the structure and function of adult haemoglobin
Example answer
Haemoglobin
Metalloprotein found within erythrocytes (RBCs)
200-300 million molecules of Hb within each RBC
Structure
Hb molecules are tetramer's consisting of four globular protein subunits
Majority of adult blood contains 2x alpha and 2x beta globular subunits (HbA)
Various other forms of Hb: HbA2 (adult), HbF (fetal), HbS (Sickle cell disease), etc.
The make up of these subunits effects their capacity to bind + transport O2
Each globular subunit is attached to one Haem group
Each haem group contains:
A protoporphyrin ring
A central ion molecule in ferrous state (Fe2+)
Function
Oxygen transport
Reversibly binds to oxygen and transports it around the body in the blood
One haem group can bind one O2 molecule (each Hb molecule binds four O2 molecules), exhibits positive cooperativity.
Amount of binding is related to PAO2 (98% at 100mmHg, 75% at 40mmhg)
98% of oxygen in the blood is carried by Hb
Carbon dioxide transport
Reversibly binds to carbon dioxide to transport it away from the tissues to the lungs
Hb contributes to the CO2 transport by 2 mechanisms
By directly forming carbo-amino compounds (30% CO2 evolved from lung)
As a proton acceptor for the RBC bicarbonate transport system (60% of CO2 evolved from lung)
Buffer
Haemoglobin is the primary protein buffering system in the blood
It exists as a weak acid (HHb) and Base (KHb)
Buffers by binding excess H+ ions to the imidazole side chains of the histidine residues
Nitric oxide regulation
Hb is important in regulating NO function
Hb readily binds NO and can inactivate or transport it, thus regulating its activity.
Examiner comments
57% of candidates passed this question.
Marks were awarded for the two components of this question – structure and function. The
structure component was often only briefly described with a cursory overview provided; however,
this component contributed around half of the available marks. Many candidates were unable to
accurately describe the structural components of the haemoglobin molecule. The functional
component was handled better – however much time was wasted with detailed drawings of the
oxyhemoglobin curve (not many marks awarded for this). The basic function of haemoglobin
carriage of oxygen and carbon dioxide was known, but detail was often missing about its role as
a buffer or its role in the metabolism of nitric oxide.
Explain resonance and its significance and the effects of damping on invasive arterial blood pressure measurement.
Example answer
Resonance
Increase in the oscillations of a vibrating system when energy is applied to the system in harmonic proportions to the natural frequency of the system
Natural frequency
Frequency at which a system oscillates when not subjected to repeated/continuous external forces, in the absence of damping
Resonance and IABP
An arterial waveform is the composite of many wave forms of increasing frequencies (harmonics)
At least 8 harmonics must be analysed to have sufficient resolution in the waveform
We do not want the arterial line system to oscillate at a frequency close to the heart rate
Commonly measured HR ranges 30 to 180/min = 0.5Hz to 3Hz
To minimise effects of resonance, the natural system of our arterial system must therefore be 8 harmonics above the frequency we are measuring (3Hz)
If 3Hz is the fastest HR we are measuring then 8x3 = 24Hz. Thus our system must be >24Hz
To increase the natural frequency of the arterial line system we can use a short, wide, stiff catheter with no bubbles in tube
Damping
Loss of energy in the system, which gradually reduces amplitude of oscillations
Dampening is used to prevent large amplitude changes due to resonance when the natural frequency of the system is close to the transducers natural frequency
There is an optimal level of damping (damping coefficient 0.64)which maximises frequency responsiveness
Degree of damping can be assessed using the square wave (fast flush) test
Overdamped (coefficient >0.7)
Falsely low SBP
Falsely high DBP
Loss of fine waveforms
MAP remains fairly accurate
Underdamped (coefficient <0.6)
Falsely high SBP
Falsely low DBP
MAP remains fairly accurate
Examiner comments
23% of candidates passed this question.
Many candidates gave detailed answers that involved the set up and components of the arterial
line system that was not asked for in the question and did not attract marks. There was confusion
around the correct use of the terms natural frequency, resonance frequency and harmonics –
candidates that were able to describe these frequencies correctly went on to achieve a good mark
– the graphs and discussion around optimal dampening, over and underdamped traces were
often drawn poorly or without sufficient detail, and at times were not used within in the context of
the answer. Descriptions of the clinical effect seen with over / under dampened traces on blood
pressure was well described.
Most candidates provided a structured answer based around a sensor / central integration /
effector model with appropriate weighting towards the sensor / integration component. Better
answers provided an understanding of details of receptor function, roles of the medullary and
pontine nuclei and how these are thought to integrate input from sensors. Marks were awarded
to PaCO2 ventilation and PaO2 ventilation response when accurate, correctly labelled diagrams
or descriptions were provided.
Deafness can occur with rapid adminsitration in large doses
Examiner comments
51% of candidates passed this question.
Most candidates presented a well-structured answer and provided a basic understanding.
Answers that provided accurate indications and details of the mechanism underlying the actions
of frusemide attracted more marks. Those recognising the increased delivery of sodium and
chloride to the distal tubule (exceeding resorptive capacity) were awarded more marks that those
answers that attributed the diuretic action solely to reduction in the medullary gradient. Frusemide
has many potential adverse effects and a reasonable list was expected. Conflicting information
was common (e.g. highly bound to albumin – Vd 4 L/kg) and better answers avoided this.
Define bioavailability (10% of marks). Outline the factors which affect it (90% of marks).
Example answer
Bioavailability
The fraction of the drug dose reaching the systemic circulation, compared to an equivalent dose given intravenously.
Can be calculated from the area under the concentration time curves for an identical bolus dose given non-intravenously (e.g. orally) and intravenously at the same time.
Pharmacogenetic differences in absorption, metabolism of drugs (e.g. isoniazid)
First pass metabolism
Drugs absorbed via GIT pass via portal vein to liver and are subject to first pass metabolism (metabolised prior to reaching systemic circulation).
May be impaired with hepatic insufficiency (increased bioavailability)
Examiner comments
49% of candidates passed this question.
Many candidates spent time defining and describing aspects of pharmacokinetics which were not
relevant to the question. E.g. clearance, volume of distribution and half-life. Candidates who
scored well utilised a structure which incorporated the headings of the factors which affect the
bioavailability of medications with a simple description as to the nature of the effect. These factors
included: the physical properties of the drug, the preparation, patient factors, the route of
administration and metabolism amongst others.
Outline the formation, circulation and functions of cerebrospinal fluid
Example answer
CSF
ECF located in the ventricles and subarachnoid space
~2ml/kg
Divided evenly between the cranium and spinal column
Formation
Constantly produced
~550ml produced per day (~24mls/hr)
Produced by
Choroid plexus (70%) - located in ventricles of brain
Capillary endothelial cells (30%)
Produced by a combination of ultrafiltration (via fenestrated choroidal capillaries) and active secretion
Na actively transported out. Gradient drives co-transport of HCO3 + Cl
Glucose via facilitated diffusion, water by osmosis
Circulation
Circulation is driven by
Ciliary movement of ependymal cells
Respiratory oscillations and arterial pulsations
Constant production and absorption
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 by the arachnoid villi
Rate of ~24mls/hr
Located predominately in the dural walls of the sagittal + sigmoid sinuses
Function as one way valves, with driving pressure leading to absorption.
Functions
Mechanical protection
The low specific gravity of CSF > decreased effective weight of the brain (1500g > 50g)
With the reduced weight
Less inertia = less acceleration/deceleration forces
Suspended > no contact with the rigid skull base
Buffering of ICP
CSF can be displaced / reabsorbed to offset any increase in ICP
Stable extracellular environment
Provides a constant, tightly controlled, ionic environment for normal neuronal activity
Control of respiration
The pH of CSF is important in the control of respiration (CO2 freely diffuses into CSF and can activate central chemoreceptors)
Nutrition
Provides a supply of oxygen, sugars, amino acids to supply the brain
Examiner comments
81% of candidates passed this question.
This is a three-part question and was marked as such. The circulation and functions of CSF was
generally well answered. Formation of CSF, however, was answered poorly, with many candidates listing its composition instead. The examiners were looking for an understanding of the physiological processes of formation not the composition
Discuss the advantages and disadvantages of the use of an intravenous infusion of fentanyl in comparison to morphine.
Example answer
Distribution
Fentanyl
Widely and rapidly distributed in tissues
Thus will accumulate in tissues with sustained infusions
Morphine
Relatively less widely distribute and thus less likely to accumulate in tissues
Context sensitive half time (CSHT)
due to the differences in distribution, fentanyl has an increased CSHT relative to morphine
Therefore, the effects of morphine are less likely to be effected by the duration of infusions, whereas with fentanyl, increasing infusions will lead to longer time to wear off and in a less predictable manner
Fentanyl = good lipid solubility = reduced CNS effect
Protein binding
Fentanyl has 90% protein binding, morphine 30%
Thus low protein in critical ilness = increased effect of fentanyl (morphine less effected)
Other pharmocodynamics
Morphine is a vasodilator (helpful in CCF, less so in septic shock)
Fentanyl has no direct cardiovascular effects
Fentanyl has a fast onset of action
Other
Fentanyl more expensive than morphine
Examiner comments
27% of candidates passed this question.
These are both level 1 drugs commonly used as an infusion in daily practice. This question specifically asked the candidates to frame their answers around an intravenous infusion of fentanyl in comparison to morphine. A tabular listing of general properties of the two drugs highlighting the differences between the drugs would not score well. The question asks for a considered response that should focus on context sensitive half-life, compartments and metabolism, instead many focused on the speed of onset and potency, which are minor considerations when drugs are given for long periods by infusion. Candidates often demonstrated a superficial knowledge of key pharmacokinetic concepts with limited application of these principles in the context of an intravenous infusion. Better answers also related the above to various relevant pharmacodynamic influences such as age, liver and renal impairment.
Increases by 50% (Due to increased TV and RR) - trimester 1
Due to left shift of PaCO2 curve by progesterone
Increases during labour due to pain
Compliance
chest wall compliance decreases due to increased abdominal contents (Trimester 1)
Lung compliance stays the same
Resistance
Increased upper airway resistance due to mucosal oedema (due to oestrogen, progesterone)
Gas exchange / tension
PaO2 increases
PaCO2 decreases (increased minute ventilation) due to progesterone induced sensitivity to CO2
Leads to compensated respiratory alkalosis (progesterone)
VO2
Increased oxygen consumption (~20%) due to increased body mass + fetus
Increases by up to 60% in labour
Post delivery
FRC and TV return to normal within 5 days
Examiner comments
31% of candidates passed this question.
The question asked for a description of the respiratory changes throughout pregnancy, which includes labour. Simple lists of changes did not score highly. A straightforward structure including; first, second and third trimester delineation would have elevated many answers from below par to a pass. Many good answers gave succinct detail on both mechanical respiratory changes and the hormonal mechanisms behind them. Higher scoring answers also described the overall effect of individual changes to spirometry, geometry or respiratory control.
The factors that influence VR are captured in 2 formulae; VR = CO, and VR = (MSFP-RAP) / Venous Resistance. Candidates that used these as the backbone structure of their answer scored well. Quite a few candidates failed to consider factors that affect left heart CO also effect VR. Recognising that CO does = VR appeared to elude some candidates.
Outline the distribution, absorption, elimination, regulation and physiological role of phosphate.
Example answer
Absorption
Normal intake = ~0.5mmols/kg/day
Absorbed in the intestine (duodenum, jejunum)
Passive mechanism = paracellular = not regulated
Active mechanism = cotransport with sodium = regulated
Distribution
85% = stored in bone/teeth
14% = intracellular
1% = extracellular fluid (half ionised, other half forms complexes/proteins)
Normal serum level = 0.8-1.2 mmol/L
Elimination
Renal
Freely filtered in kidney
Most is reabsorbed in proximal and distal tubules
2/3 of phosphate that is lost, is lost renally
Stool
1/3 lost in stools
Regulation
Calcitriol
Increased bone reabsorption
Increased Intestinal absorption
Increased Renal reabsorption
PTH
Decreased renal reabsorption
Increased bone resorption
Net effect =decrease in serum phosphate
Thyroxine
Increased renal reabsorption
Glucocorticoids
Decreased renal reabsorption
Role
Structural role
bone and teeth formation
Phospholipids of cell membranes, DNA, RNA
Regulatory role
Second messenger (IP3)
Metabolic role
Synthesis of ATP
Acid base regulation (urinary and intracellular buffering)
cofactor in oxygen transport (2-3 DPG)
Examiner comments
29% of candidates passed this question.
The answer structure should have utilized the headings provided in the question. Many candidates described the physiology of calcium, which while related, did not attract marks. The distribution section required not only the sites of distribution but also the percentages found in each. The regulation should have included both primary and secondary mechanisms and an outline on the factors affecting renal excretion, intestinal absorption and release from bone etc. An outline of the physiological role of phosphate required a broad knowledge of physiological processes.
Describe the physiological consequences of the oral ingestion of 1 litre of water in a young adult.
Example answer
Handling of oral water ingestion
Absorption
Near complete absorption of water occurs in the proximal small intestine (85%), with 10% in large bowel, 5% in rectum.
Most of the diffusion is transcellular and driven by osmosis (due to active absorption of other electrolytes, including sodium)
Distribution
Absorbed water distributes equally amongst all body fluid compartments, proportional to size
~66% into the ICF (~667mls)
~33% into the ECF (~333mls)
~75% of which is interstitial fluid
~21% of which is intravascular
~4% of which is transcellular fluid
Elimination
Water is eliminated predominately by renal excretion
Filtered water at the glomerulus is highly regulated
Physiological consequences of oral water ingestion
Decrease in osmolality
~2.5% decrease in osmolality for 1L of oral water
Sensed by osmoreceptors (hypothalamus) which have sensitivity of ~2% > decrease in secretion of vasopressin from the posterior pituitary gland
Decreased vasopressin > decreased luminal aquaporin channel insertion in collecting ducts of nephrons > decreased water reabsorption > diuresis
Decrease in plasma Na concentration
Leads to release of angiotensin and aldosterone > increased Na reabsorption in nephron
Small increase in blood volume
For 1L oral ingestion of water > leads to ~70mls of intravascular water (33% of 1L goes to ECF, 21% of which is intravascular)
This change is below the sensitivity threshold of the cardiovascular regulatory reflexes > no change in blood pressure/HR of a normal healthy individual
Examiner comments
28% of candidates passed this question.
It was expected candidates would provide details the consequences of water ingestion from its rapid absorption in the small intestine to the resultant impact on plasma osmolarity and the minimal impact of plasma volume of this volume. Some detail on the mechanisms of absorption (transcellular vs osmosis) was expected and the distribution of water across body fluid spaces. Many candidates accurately described the small drop in plasma osmolarity that is sufficient to trigger osmoreceptors with better answers providing details of the locations and mechanisms involved. The physiological consequences of inhibition of ADH, including the renal effects of decreased water permeability in distal renal tubules and collecting ducts. The volume load after distribution would be lower than the plasma volume triggers for the circulatory reflex responses.
Kidneys have the capacity to autoregulate (cortical nephrons can, juxtamedullary nephrons cant)
Can maintain a constant RBF across a wide range in MAP (70-170mmHg)
Two main mechanisms: myogenic autoregulation, tubuloglomerular feedback
Myogenic autoregulation
Intrinsic contraction of the afferent arterioles in response to increased transmural pressures via release of vasoactive mediators
Tubuloglomerular feedback
Increased RBF > increased GFR > increased Na/Cl sensed by macula densa > releases adenosine > constriction of afferent arterioles > decreased RBF
Decreased RBF > decreased GFR > decreased Na/Cl at macula densa > releases NO > dilation > increased RBF
SNS
Activation of adrenoreceptors > constriction of arterioles > decreased RBF
Hormonal response
Renin is released by B1 stimulation and decreased GFR
AG2 constricts afferent and efferent arterioles > decreased flow
Impact of adrenoreceptor agonists on RBF
As mentioned, kidneys are innervated by SNS (adrenergic receptors)
Massive SNS stimulus (e.g. shock, high dose adrenergic agonists) can override autoregulation
Efferent arterioles constrict greater than afferent arterioles > decrease in RBF, but the GFR is proportionally less effected (greater perfusion pressure)
Effect of alpha adrenergic agonists
Will act as renal vasoconstrictors > decrease renal blood flow / GFR
Examples: phenylephrine, metaraminol
Effect of beta adrenergic agonists
Will lead to increased RBF (vasodilator)
Example: isoprenaline
Non-selective adreneergic agonists
Greater proportion of alpha > beta receptors.
Mixed agonists (e.g. adrenaline) will predominately lead to decreased flow (alpha predominance)
Examiner comments
64% of candidates passed this question.
This question was well answered by most candidates. The description of renal flow involves a brief comment of the anatomy including interlobar, arcuate, interlobular arteries, then afferent and efferent arterioles – 2 sets of capillaries and then corresponding veins and better answers made the distinction better cortical and medullary flow and went on to detail the consequence of this. Renal blood flow is autoregulated and most candidates describe well the various mechanisms around myogenic and tubuloglomerular feedback. Additional marks were gained with by discussing renal vascular resistance and how this may be varied. The impact of adrenoreceptor agonists is varied but generally sympathomimetic agents will vasoconstrict and therefore increase renovascular resistance and result in a decrease renal blood flow. The relative impact on afferent vs efferent arteriolar tone may alter glomerular perfusion pressure.
Describe the relationship between muscle length and tension (50% of marks). Outline the physiologic significance of this relationship in cardiac muscle (50% of marks).
Example answer
Length-tension relationship
The tension generated within a single muscle fibre is related to its length
Total tension = passive tension + active tension
Passive tension
Increases with increasing muscle length (modelled as a non-linear spring)
Active tension
Also varies with muscle length, but is described by the sliding filament model and has an optimal length at which maximal tension is generated
The physiological basis of this is due to different number of actin-myosin cross bridges formed at the different muscle lengths
The optimal myocardial sarcomere length is ~2.2 um (greatest overlap of actin-myosin filaments)
The resting muscle length is often close to the optimal length for active tension
Cardiac muscle
The muscle length-tension relationship forms an important part of the Frank-Starling law (strength of myocardial contraction is dependant on the initial muscle fibre length)
With increase in diastolic filling of the heart > increase stretch (preload) > increased muscle length (increased cross bridge formation) > increased force of contraction > increased stroke volume
Note: this mechanism is within limits. When the muscle length is too great, there is actually a reduction in cross bridge formation > decreased SV
Importance
Ensures venous return = cardiac output (else pooling would occur)
Allows beat-beat adjustments to variation in preload
Examiner comments
41% of candidates passed this question.
Some detail was expected on a general description that tension is variable with the length of muscle. It was expected answers would describe that there is a resting length at which tension developed on stimulation is maximal. Many candidates omitted that differences exist between muscle types with smooth muscle behaving differently. Additional credit was given for the distinction about active tension vs resting tension. It was expected a description of the potential mechanism would be included with discussion of sliding filament theory, overlapping fibres and optimal sarcomere length. Some candidates utilised a diagram effectively to convey understanding and more detail was rewarded with additional marks.
The second half of the question involved describing how this relationship is particularly important in cardiac muscle and underpins the Frank Starling relationship and all the cardiac physiology that follows. Initial length of fibres is determined by the diastolic filling of the heart, so pressure developed is proportionate to the total tension developed. The developed tension increases as diastolic volume increases to a maximum (the concept of Heterometric regulation). Better answers appreciated that the physiology may be different for a whole heart rather than isolated muscle fibres.
Outline the pharmacology of intravenously administered magnesium sulphate
Example answer
Name
Magnesium sulphate
Indications
HypoMg, eclampsia/pre-eclampsia, severe asthma, arrhythmias (including TdP), analgesia
Pharmaceutics
Clear colourless solution, various concentrations
Routes of administration
IV, IO
Dose
10-20mmols
Pharmacodynamics
MOA
Essential cation
- Essential cofactor in hundreds of enzymatic reactions
- Necessary in several steps of glycolysis (ATP production)
- NMDA receptor antagonism (increasing seizure threshold)
- Inhibits Ach release at NMJ
- Smooth muscle relaxation (Inhibits Ca L-type channels)
Effects
CNS: anticonvulsant
Resp: Bronchodilation
CVS: Anti-arrhythmic
Side effects
Related to speed of administration + degree of HyperMg (dose dependant)
Urine; clearance is proportional to GFR and plasma concentration
Special points
Incompatible with calcium salts > precipitation
Drug interaction with NMB agents (potentiation)
Examiner comments
55% of candidates passed this question.
Overall answers were well structured. However, a lack of detail and inaccurate pharmacokinetics was common. Better answers included a discussion of the mechanism of action of Mg++ including Ca++ antagonism, presynaptic cholinergic effects and NMDA receptor antagonism. Adverse effects were not discussed in detail by many candidates and contraindications were commonly omitted.
Right lateral: thyroid, right common carotid a., right vagus nerve, azygous vein. Eventually the right lung and pleura,
Left lateral: thyroid, left common carotid, arch of aorta, left subclavian artery, left recurrent laryngeal nerve. Eventually the left lung and pleura,
Bronchi
Left main bronchi
5cm long, courses leftward
More horizontal and smaller diameter than right main bronchi
Better answers included details of the significant structures related to the cervical and mediastinal trachea and bronchi. The lobar branches and bronchopulmonary segments requiring naming to attract full marks. Many answers lacked sufficient detail or contained inaccuracies regarding vertebral levels and key structural relations. Some candidates discussed the general anatomy of the airway, including the larynx, structure of the airways, blood supply and innervation. This did not attract marks.
TV regurg > increased CVP (retrograde transmission of RV systolic pressure)
TV stenosis > increased CVP (increased resistance to RV inflow)
Intrathoracic pressure
ITP is transmitted to the central venous compartment
Thus, increased PEEP, PPV, or a tension pneumothorax will lead to increased CVP
Measurement technique
Level of the transducer will clearly influence the CVP measured
Timing of the measurement with respiratory cycle
Examiner comments
18% of candidates passed this question.
It was expected that answers include central venous blood volume, central venous vascular compliance, intrathoracic pressure and tricuspid valvular function. Good answers outlined how each of these factors determine CVP and whether it was increased or decreased. Many candidates incorrectly described the effect of venous return.
Define closing capacity (10% of marks). Describe the factors that alter it (30% of marks), its clinical significance (30% of marks) and one method of measuring it (30% of marks).
Example answer
Closing capacity
The point in expiration when the small airways begin to collapse
Small airway closure occurs because the elastic recoil of the lung overcomes the negative intrapleural pressure keeping the airway open.
More likely to occur in dependant parts of the lung where airways are smaller (due to effects of gravity).
Measured using the single breath nitrogen washout test
Subject exhales to residual volume
Pure oxygen inhaled to TLC
Subject breaths out through a nitrogen sensor (records N2 concentration vs time curve)
Phase 4 of this curve indicates the closing volume.
Residual volume
Cannot be directly measured
FRC is first calculated by body plethysmography (or other methods)
ERV measured using spirometry
Residual volume is the difference between FRC and ERV
Examiner comments
49% of candidates passed this question.
Many candidates confused the factors that affect closing capacity (CC) with factors which affect functional residual capacity (FRC). Some candidates confused airway closure with expiratory flow limitation secondary to dynamic airway compression. A good answer would have included the following:
Small airway closure occurs because the elastic recoil of the lung overcomes the negative intrapleural pressure keeping the airway open. Thus, airway closure is more likely to occur in dependant parts of the lung where airways are smaller. Normally closing capacity is less than FRC in young adults but increases with age. Closing capacity becomes equal to FRC at age 44 in the supine position and equal to FRC at age 66 in the erect position. Closing capacity is increased in neonates because of their highly compliant chest wall and reduced ability to maintain negative intrathoracic pressures. In addition, neonates have lower lung compliance which favours alveolar closure. Closing capacity is also increased in subjects with peripheral airways disease due to the loss of radial traction keeping small airways open.
The consequences of airway closure during tidal breathing include shunt and hypoxaemia, gas trapping and reduced lung compliance. In addition, cyclic closure and opening of peripheral airways may result in injury to both alveoli and bronchioles. Closing volume (CV) may be measured by the single breath nitrogen washout test or by analysis of a tracer gas such as xenon during a slow exhaled vital capacity breath to residual volume. Residual volume (RV) cannot be measured directly but is calculated as follows: the FRC is measured using one of three methods: helium dilution, nitrogen washout or body plethysmography. The expiratory reserve volume (ERV) may be measured using standard spirometry. Using the measured FRC and ERV we may calculate RV from the equation:
RV = FRC – ERV. Then CC = RV + CV.
Systemic corticosteroids should be given to all mod-severe asthma > improve outcomes
MOA: bind to cytoplasmic glucocorticoid receptors > change in gene transcription > down-regulates the synthesis of proinflammatory cytokines/mediators
Effects: increased B receptor responsiveness, decreased inflammation, decreased mucus secretion
Side effects: numerous! Depends on dose/duration. Examples:
Short term: hyperglycaemia, hypokalaemia, immunosuppression, insomnia/confusion/psychosis,
Long term: cushings, osteoporosis, skin thinning, weight gain, immunosuppression
Other potential treatment options (and MOA)
Magnesium sulphate > inhibits L type calcium channels > bronchodilation/SM relaxation
Ketamine >inhibits L type calcium channels > Bronchial smooth muscle relaxation
Aminophylline > PDEI > SM relaxation / bronchodilation
Heliox > Improves laminar airflow > may improve ventilation
Examiner comments
29% of candidates passed this question.
Answers should have included the most important aspects of the pharmacology of the most commonly used drugs e.g. class, mechanism of action, pharmacodynamics and important adverse reactions. More information on beta-agonists and corticosteroids (mainstays of management) was expected than drugs like magnesium, ketamine and other adjunctive treatments.
Dose depends on many pt. factors. 1-5mg premedication. 2.5-10mg seizures. Infusions.
RSI 1-2mg/kg. Infusion (4-12mg/kg/hr)
pKa
6.5
11 (almost completely unionised)
Propofol has higher pKa
Pharmacodynamics
MOA
Allosteric modulator of GABAA receptors (ionotropic ligand gated channel) in the CNS. Binds to distinct site from GABA. Leads to Cl enters > hyperpolarisation.
Propofol binds to B subunit of GABAA receptor > Cl enters > hyperpolarisation
CNS: depression, pain injection site
CVS: decreased SVR > hypotension, bradycardia
MET: high lipids
Both cause cardiovascular instability and respiratory depression
Pharmacokinetics
Onset
peak effect 2-3 minutes (IV)
Seconds
Propofol has faster onset / offset
Absorption
~40% oral bioavailability
Absorbed well, but sig. 1st pass metabolism
IV Only (high first pass metabolism)
Propofol is IV only
Distribution
95% protein bound, very lipid soluble
Vd = 1L / kg
98% protein bound
VOD 2-10L/kg
Readily crosses BBB
Both highly protein bound.
Metabolism
Hepatic metabolism by hydroxylation
Active (1-a hydroxymidazolam) and inactive metabolites
Hepatic > inactive metabolites (glucuronides and sulphates)
Both metabolised by liver. Midaz has active metabolites
Elimination
Renal excretion
T 1/2 = 4 hours
Renal excretion
Bolus T1/2 - 120s.
Special points
Flumazenil - antagonist (reversal agent)
No reversal agent
Examiner comments
77% of candidates passed this question.
Highlighting important similarities and differences between the drugs scored higher marks than listing the pharmacology of each drug separately. More pharmacokinetic information was required than simply stating both drugs “are metabolized in the liver and excreted by the kidneyâ€.
Describe the principles of capnography, including calibration, sources of error and limitations.
Example answer
Capnography
The graphical display of expired CO2 concentration over time
This is different to ETCO2 (which is the CO2 concentration at end-expiration) and capnometry (which is the measurement of CO2 concentration)
Measurement / Principles
CO2 concentrations (capnometry) is measured in clinical practice using infrared spectroscopy and applying the principles of the Beer-Lambert Law
The concentration of CO2 is measured by exploiting the differences in CO2 absorption of light in the NIR spectrum. With the degree of absorption related to concentration of substance.
Imidazole side chains can bind hydrogen ions and can buffer against change to pH
Anticoagulant
Has heparin like activity. Low albumin attenuates fibrinolysis
Protein store:
~50-60% of plasma protein
Anti-oxidant effect
Abundant in thio groups which readily scavenge reactive oxygen and nitrogen species
Inflammatory marker
Negative phase protein (decreases in response to inflammation)
Examiner comments
30% of candidates passed this question.
A good answer began with a definition of plasma and then listed the components - water, albumin, globulins, fibrinogen and other proteins before mentioning the lipid content, nutrient content, wastes and electrolytes. Frequently the breakdown of the globulin component was inaccurate. A common omission was dissolved gas components. Descriptions of the calculation of oncotic pressure and GFR were not asked and hence did not attract marks.
The functions of albumin may be subdivided into: Osmotic pressure, transport function, acid-base buffer, anti-oxidant, anticoagulant effect, protein store, metabolism and 'other'.
Define pain. Outline the processes by which pain is detected in response to a peripheral noxious stimulus
Example answer
Pain
"An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage" (IASP, 2020)
Can be broadly classified by duration (e.g. acute vs chronic) or aetiology (e.g. visceral vs neuropathic)
PAIN PATHWAY
Nociceptors
Free unmyelinated nerve endings which convert noxious stimuli into action potentials (APs)
Activation
Activated by thermal, mechanical, and chemical stimuli
Sensitised by inflammatory mediators (e.g bradykinin, histamine, Substance P)
Leads do conformational change in nociceptor > ion channel opening > depolarisation
Relay APs from the nociceptor receptor to the dorsal horn of the spinal cord (primary afferent)
Neuron may travel up/down the tract of Lissauer 1-2 levels prior to synapsing in the dorsal horn
Two types of nociceptor neurons
Type A<math display="inline">\delta</math> fibres
Impulses from mechanical and thermal stimuli
Large, myelinated, fast (40m/s)
Type C fibres
Impulses from thermal, mechanical and chemical stimuli
Small, unmyelinated, slow (2m/s)
Second order neurons (afferent)
Synapse with primary afferents in Dorsal horn
Decussates in the anterior commissure, ascends in the spinothalamic tract, synapses in the thalamus with third order neurons
Third order neuron (afferent)
Relays information from the thalamus to the cerebral cortex for central processing of pain
PAIN MODULATION
Descending inhibition
Neurons from periaqueductal grey matter project to the spinal cord
Noradrenaline and serotonin are main neurotransmitters
Have inhibitory effects on the synapse of 1st/2nd order neurons
Segmental inhibition
Initially thought to be due to gate control theory
Now other mechanisms though to be responsible
Endogenous opioid system
(e.g. endorphins) which can bind to opioid receptors > reduced nociception
Examiner comments
33% of candidates passed this question.
Starting with the WHO definition of pain, followed by a brief description of the nature of noxious stimuli (thermal, mechanical, chemical) then proceeding to mention the nature of the cutaneous receptors would have been a very good start to this question. Following this, a description of the various substances involved in pain (K, prostaglandins, bradykinin, serotonin, substance P) and outlining the types of nerve fibres involved in pain transmission and how they synapse in the spinal cord and cortex was expected. The presence and nature of the descending inhibitory pathways was mentioned by very few.
Mediated by secretin (released from S cells of duodenum) and CCK (enteroendocrine cells in duodenum)
Major factor which leads to increased secretion of pancreatic juice.
Inhibitory factors
Glucagon
Somatostatin
Examiner comments
33% of candidates passed this question.
Most candidates were able to mention some pancreatic enzymes, though often in insufficient detail to attract full marks. The amount, type, pH, etc. of pancreatic secretions was often not included. Many candidates did not describe the stimuli for pancreatic secretion. Better answers described the cephalic, gastric and intestinal phases of pancreatic secretion.
Outline the classification and effects of beta-blocking drugs with examples (50% of marks). Compare and contrast the pharmacokinetics of metoprolol with esmolol (50% of marks).
Example answer
Classification of beta blockers
All beta blockers are competitive antagonists
Can be classified according to
Receptor selectivity
Non selective (B1 and B2) e.g. sotalol, propranolol
B1 selective e.g. metoprolol, esmolol, atenolol
A and B effects: labetalol, carvedilol
Membrane stabilising effects
Stabilising e.g. Propanolol, metoprolol, labetalol
Non stabilising e.g. atenolol, esmolol, bisoprolol
Intrinsic sympathomimetic activity
ISA e.g. labetalol, pindolol
Non ISA e.g. metoprolol, sotalol, propranolol, esmolol
- Hydrolysis by RBC esterase > inactive metabolites
Elimination
Renal excretion
T 1/2 approx 4 hours
Renal excretion
T 1/2 10 mins
Examiner comments
47% of candidates passed this question.
Beta-blocking drugs were generally well classified. Selectivity, membrane stabilising activity and ISA should have been mentioned. Many candidates omitted or poorly answered the ‘effects’ of beta blockers. Candidates who performed well answering the pharmacokinetics of metoprolol and esmolol provided a table of the two drugs. Superficial statements such as “hepatic metabolism and renal excretion†attracted minimal marks. The mechanism of action of beta blockers was not requested
Effect of hepatic blood flow changes in relation to HER
For drugs with low ER (e.g. diazepam, warfarin) increasing QH leads to:
Minimal increase in clearance (capacity limited)
Decreased hepatic ER (more pronounced relatively)
For drugs with high ER (e.g. propofol and GTN) increasing QH leads to:
Marked increase in clearance (flow limited)
Decreased hepatic ER (less pronounced relatively)
Role of liver in drug clearance
Liver is heavily involved in drug metabolism
Phase 1 metabolic reactions
Involves oxidation (loss of electrons), reduction (gain of electrons) and hydrolysis (addition of H2O molecule)
Driven predominately by the Cytochrome p450 system and esterases in liver
E.g. metabolism of Propofol, benzodiazipines, opioids, volatiles anaesthetics
There can be significant variability in activity of CYP enzymes which leads to variability in drug response (e.g. CYP2C19 polymorphism > variability in phenytoin and clopidogrel metabolism)
Phase 2 reactions
Involves conjugation (increasing water solubility)
Clearance was generally well answered. It is the volume of plasma cleared of a drug per unit time, not the mass of drug cleared. An equation was helpful in identifying the relevant components of hepatic clearance.
ClHep=QH X ERHep
ERHep= FU x ClInt / QH + FU x ClInt
QH = hepatic blood flow
ERHep = hepatic extraction ratio
FU = fraction of drug unbound in plasma
ClInt = hepatic enzymatic capacity
Many candidates did not describe the effects of hepatic blood flow and intrinsic clearance on drugs with high and low hepatic extraction ratios. Some discussion of Phase I and II reactions was also expected.
The question sought information on the structure (anatomy), function (physiology) and vascular supply of the right and left ventricle. Good answers provided detail in each section e.g. values for ventricular pressure rather than simply stating “high- and low-pressure systemsâ€.
Many marks may be gained by a simple anatomical description & labelled PV loop for each ventricle. Many candidates focussed solely on the coronary circulation, to which only a proportion of the marks were allocated.
Chest wall and lung compliance are roughly equal in healthy individual
Normal compliance of the respiratory system is approximately 200mls.cmH2O
Static compliance
Compliance of the respiratory system at a given volume when there is no flow
Dynamic compliance
Compliance of the system when there is flow (respiration)
Will always be less than static compliance due to airway resistance
At a normal RR is approximately equal to static compliance
Specific compliance
The compliance of the system divided by the FRC
Allows comparisons between patients which are independent of lung volumes
Factors effecting compliance
Chest wall
Increased
Collagen disorders such as Ehlers-Danlos syndrome
Cachexia
Rib resection
Decreased
Obesity
Kyphosis / scoliosis / Pectus excavatum
Circumferential burns
Prone positioning
Lung compliance
Increased
Normal ageing
Emphysema
Upright posture
Lung volume (highest compliance at FRC)
Decreased
Loss of surfactant (E.g. ARDS, hyaline membrane disease)
Loss of functional lung volume (e.g. pneumonia, lobectomy, pneumonectomy, atelectasis)
Pulmonary venous congestion (pHTN) and interstitial oedema (APO)
Reduced long elasticity (e.g. Pulmonary fibrosis)
Positioning (e.g. supine positioning)
Examiner comments
51% of candidates passed this question.
Answers were generally well structured. Better answers described lung and chest wall compliance and the pressures which are used to calculate compliance. Better answers displayed an understanding of dynamic, static and specific compliance and provided a reasonably comprehensive list of the physiological factors affecting chest and lung compliance.
Readily metabolised intro adrenaline by MAO and COMT
Not metabolised
Elimination
Excreted in urine as inactive metabolites (>85%).
Half life ~2 mins
Minutes, renal elimination
Special points
Tachyphylaxis (slow)
Effect exaggerated in patients taking MAOI (less breakdown)
Tachyphylaxis (fast( with infusion))
Examiner comments
71% of candidates passed this question.
Marks were distributed across pharmaceutics, uses, dose & administration, mechanism of action, Pharmacokinetcs and Pharmacodynamics. Common omissions were doses/rates of infusion, effects other than on heart/SVR (e.g. splanchnic, renal blood flow), indirect effect of metaraminol, receptor effect of noradrenaline other than alpha 1 and tachyphylaxis.
Organophosphate poisoning
Counteract muscarinic effects of anticholinesterases
drying of secretions
Pharmaceutics
Clear colourless solution. 600mcg/ml. Racemic mixture with the L-isomer being active
Routes of administration
IV, IM, topical (eye)
Dose
600mcg - repeated administration can be given
Pharmacodynamics
MOA
Competitive antagonism of muscarinic anticholinergic receptors
Effects
CVS: increased HR (and CO), decreased AV conduction time
RESP: bronchodilation
GIT: Drying of secretions
Side effects
CNS: Hallucinations, confusion, amnesia, delirium, central anticholinergic syndrome
GIT: dry mouth, delayed GIT motility
CVS: may cause initial transient bradycardia when given slowly
MSK: inhibits sweating
Pharmacokinetics
Onset
Seconds. Duration 2-3hours
Absorption
IV
Distribution
50% protein bound. VOD=3L/kg. Crosses blood brain barrier and placenta
Metabolism
Extensive hepatic hydrolysis into tropine and tropic acid
Elimination
Renal elimination of metabolites. T 1/2 approx 2 hours
Special points
Examiner comments
53% of candidates passed this question.
Most candidates used a good structure to compose their answer. Better candidates understood that CNS effects occur as atropine is a tertiary amine that crosses the blood brain barrier. The mechanism of action was required. Indications for use should have included bradycardia, organophosphate poisoning, drying of secretions etc. Reasonably extensive details regarding pharmacodynamics was expected, including potential toxic effects. There was limited knowledge regarding pharmacokinetics.
Compare the pharmacology of piperacillin-tazobactam and ciprofloxacin
Example answer
Name
Piperacillin-Tazobactam
Ciprofloxacin
Class
Semi-synthetic penicillin (piperacillin)
B-lactamase inhibitor (tazobactam)
Fluroquinolone
Indications
Pseudomonal infection
Broad spectrum antimicrobial cover of severe infections/sepsis
Effective for many infections (skin, joint, gastro, UTI, LRTI)
Pharmaceutics
Powder, reconstitutes in water/NaCl/glucose
Tablet (250-750mg) or yellowish powder for dilution.
Routes of administration
IV/IM
IV, PO
Dose
4g/0.5g 8hrly or 4g/0.5g 6hrly (pseudomonas cover)
Dose reduced renal failure
250-750mg BD (PO), 200-400mg BD/TDS (IV)
Pharmacodynamics
MOA
Piperacillin: bactericidal - inhibits cell wall synthesis by preventing cross linking of peptidoglycans by replacing the natural substrate (D-ala-D-ala) with their B-lactam ring
Tazobactam: B lactamase inhibitor (prevents piperacillin degradation)
Bactericidal - Inhibits DNA gyrase and topoisomerase IV > inhibits DNA synthesis
Very good tissue penetration (minimal CNS without active inflammation)
Low protein binding (<30%)
Low protein binding (25%). Great tissue penetration. VOD 2.5L/kg.
Metabolism
Piperacillin: not metabolised
Tazobactam: metabolised to M1, an inactive metabolite
Limited hepatic metabolism (15%)
Elimination
Renal (80% unchanged)
T 1/2 2 hrs
Renal excretion of metabolites. T1/2 3-5 hours.
Special points
Removed by haemodialysis
Worldwide resistance to quinolones is increasing
Examiner comments
58% of candidates passed this question.
This question was most effectively answered using a tabular format. Only a minority of candidates demonstrated a comprehensive knowledge of these level 1 drugs and very few candidates compared the two in areas which lent themselves to comparison. The spectrum of activity generally lacked detail. Few candidates mentioned that piperacillin-tazobactam had superior gram-positive cover, both have extensive gram-negative cover including Pseudomonas. Piperacillin-tazobactam is effective against anaerobes; whilst ciprofloxacin has some atypical cover against Mycoplasma.
The mechanism of action was generally well described for piperacillin; many candidates incorrectly stated the mechanism of action for ciprofloxacin, confusing the drug with a macrolide. Better answers included time- dependant and concentration-dependent killing. The concept of half-life was frequently confused with the dosing interval.
Minimal marks were awarded for “allergy†and “gastrointestinal side-effectsâ€. Better candidates mentioned Liver function derangement, neutropenia, interstitial nephritis for piperacillin and tendonitis for ciprofloxacin.
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.
Right lateral: thyoid gland (lobe), carotid sheath ( common carotid, vagus, IJV), RLN
Left lateral: thyroid gland (lobe), carotid sheath ( common carotid, vagus, IJV), RLN
Neurovascular supply
SNS: sympathetic trunks
PSNS: recurrent laryngeal and vagus nerves
Arterial supply: Branches from inferior thyroid arteries
Venous drainage: Inferior thyroid veins
Surface anatomy of anterior neck (superior --> inferior)
Hyoid bone (C3)
Thyroid cartilage
Cricothyroid membrane
Cricoid cartilage (C6)
Thyroid gland
Sternohyoid muscle just lateral to the midline structures, overlies sternothyroid and thyrohyoid
Layers of dissection in tracheostomy (from anterior --> posterior)
Skin
Subcutaneous tissue
Fat
Pretracheal fascia
Fibroelastic tissue between tracheal cartilage rings
Trachea
Examiner comments
79% of candidates passed this question.
Answers required a description of the surface anatomy outlining the midline structures including
the hyoid bone and cartilages. The tissue layers should have been mentioned as should the
relevant tracheal anatomy. The anterior, posterior and lateral relations of the trachea should
also have been included along with the relevant nerves and blood vessels. Diagrams were not
essential but could have been included.
Candidates should note that marks were not awarded for a description of how to perform a
tracheostomy.
Antiarrhythmic (Class III), though other class (I, II, IV) activity
Indications
tachyarrhythmias (e.g. AF, SVT), heart failure
Tachyarrhythmias (e.g. SVT, VT, WPW)
Pharmaceutics
62.5mcg/250mcg (PO tablets)
25/250 mcg/ml (IV)
100-200mg tablets
Clear solution in ampoules (150mg) for dilution in dextrose
Routes of administration
IV and PO
IV and PO
Dose
Generally load with 250-500mcg, then 62.5-125mcg daily thereafter. Digoxin level (0.7 - 1.0) for most conditions.
IV: 5mg/kg, then 15mg/kg infusion / 24hrs.
Oral: 200mg TDS (1/52) > BD (1/52) > daily
pKA
7.2
6.6 (highly lipid soluble)
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
- Blocks K channels (Class III effects) prolonging repolarisation and therefore refractory period.
- Decreases velocity of Phase 0 by Blocking Na channels (Class I effects)
- Non-competitive inhibition of Ca channels prolonging depolarisation + AV nodal conduction time (Class IV effects)
- Slows AV/SA nodal conduction via anti-adrenergic activity (Class II effects)
Side effects
CVS: May worsen arrhythmia (lead to VF), AV block, shortened QT interval, scooped ST, TWI, bradycardia
2-3 hours (PO), 10-30mins (IV), duration of action 3-4 days
Immediate (IV), 4 hours (PO)
Absorption
80% oral bioavailability
PO bioavailability 40-60%
Distribution
Protein binding 25%
VOD 6-7L/kg
Highly protein bound (>95%)
VOD: ~70L /kg
Metabolism
Minimal hepatic metabolism (15%)
Hepatic (CYP3A4) with active metabolites (desmethylamiodarone)
Elimination
T 1/2 48 hours
urine excretion (70% unchanged)
T 1/2 = 1 month
Faces, urine, skin
Special points
Reduce dose in renal failure, monitor with dig level. not removed by dialysis
Amiodarone increases digoxin level (by preventing renal excretion and lowering protein binding)
Examiner comments
82% of candidates passed this question.
Most candidates had a good structure for answering this question; a table was commonly used.
Marks were awarded for indications and an explanation of the mechanism of action of both
drugs, which was generally well explained. The pharmacodynamic effects were often listed in a
general manner and more detail would have achieved a higher mark, including a list of the ECG
effects. Some detail on the pharmacokinetics and adverse effects of the drugs was expected
and this section was generally well answered. Better answers noted digoxin levels and potential
drug interactions.
Explain the causes of the differences between measured end tidal and arterial partial pressures of carbon dioxide (CO2).
Example answer
ETCO2 - PaCO2 gradient
There is normally a gradient between PaCO2 and ETCO2 of 0-5mmHg (where ETCO2 is lower)
The difference between the values is due to alveolar dead space
Alveolar dead space is due to alveoli which are ventilated but not perfused (e.g. west zone 1 lungs)
These alveoli do not participate in gas exchange (there is no perfusion), thus contain very little CO2 and a lot of O2 (the same amount as in inspired air)
This relatively CO2 deplete gas mixes with the rest of the expired gas, diluting the ETCO2 reading, thus leading to an observed discrepancy
Note: It is not due to anatomical dead space as this gas has already been washed out in the early stages of exhalation and thus does not contributed to ETCO2
Healthy/awake patients have near zero alveolar dead space, so near zero gradient
Factors affecting ETCO2 - PaCO2 gradient
Changes in pulmonary perfusion
Global reduction in pulmonary perfusion
e.g. pHTN, heart failure, Cardiac arrest, Severe shock
Regional decreases in pulmonary perfusion
e.g. pulmonary embolism, fat embolism
Changes in ventilation
Excessively high PEEP --> increased West Zone 1
Measurement error
Inline HME filters
Timing of measurement (measuring before end-expiration)
Poor / loss of ETCO2 calibration
Interference from other gases (e.g. N2O and collision broadening)
Physiological factors
Increasing age > increased gradient
Examiner comments
29% of candidates passed this question.
The answer required an explanation of the causes of the difference between the PaCO2 and ETCO2. This required recognising how the end point of phase 3 of the capnograph trace corresponds with end tidal CO2. The difference is caused by the alveolar dead space. The difference is normally very small in healthy adults with the ETCO2 being lower than the PaCO2. It is increased with increasing alveolar dead space. Many incorrectly attributed anatomical dead space as a contributor to the PaCO2-ETCO2 gradient. Discussion of the various types of dead space did not score marks. Marks were awarded for the processes that cause an increased gradient e.g. low cardiac output and pulmonary embolism. Recognising physiological factors such as increasing gradient with increasing age scored marks. Marks were not awarded for descriptions on how dead space is measured.
- Midaz exhibits tolerance, withdrawal, dependence, ketamine does not.
Examiner comments
62% of candidates passed this question.
In addition to the key PK and PD properties of each drug, a clear comparison was required to score well (why choose one drug over the other?). When a table was used the addition of a comparison column was helpful. A good answer covered the following: ketamine has analgesic properties whilst midazolam does not; ketamine preserves airway reflexes and does not cause respiratory depression unlike midazolam; whilst ketamine increases cerebral blood flow and CMRO2, midazolam decreases t; ketamine has a direct myocardial depressant effect which is often offset by an increase in sympathetic tone, whilst midazolam has no direct cardiac depressant effects but may reduce BP due to reduced SVR; midazolam has anticonvulsant properties, ketamine does not; ketamine is a bronchodilator; both drug effects are offset by redistribution; midazolam is lipophillic at body pH and will accumulate with prolonged infusions, ketamine will not; both are metabolised in the liver; midazolam can be reliably reversed by flumazenil, whereas there is no reliable complete reversal of ketamine; midazolam exhibits tolerance, dependence and withdrawal, whereas patients will only experience tolerance to the analgesic properties of ketamine. “Drugs in Anaesthesia and Intensive care†chapters on midazolam and ketamine outline the key facts to include in this answer; interpretation and comparison of these facts will help achieve a good mark.
CO2 dissolves into RBC and leads to H+ and HCO3 (per above equation)
HCO3 moves into plasma, H+ binds to reduced (deoxy) Hb
Cl moves into the cell to maintain electroneutrality (chloride shift)
When Hb is oxygenated in the lungs, H+ dissociates and coverted back to CO2 by the above equation and is exhaled
Haldane effect accounts for the increased capacity of Hb to carry CO2 when poorly oxygenated
Carbamino compounds
Accounts for
~5% of the CO2 in the blood
~30% of the CO2 evolved by the lung
Formed by the combination of CO2 with terminal amine groups in blood proteins
Haemoglobin is the most abundant protein and has most imadazole side chains (greatest carrier capacity)
The reaction occurs faster with deoxHb than oxy-Hb (Haldane effect)
Examiner comments
65% of candidates passed this question.
A definition of arterial and venous CO2 content (mls and partial pressure) and an outline of the 3 forms of CO2 in the blood and their contribution to the AV difference, followed by a detailed explanation of each form of carriage was required for this question. A good answer included a table of the contribution of each form of carriage to arterial and venous content and the AV difference; explained the concepts of chloride shift when describing carriage as HCO3 -; detailed the Haldane effect and its contribution to carbamino carriage and referenced Henry’s law when describing dissolved CO2. West’s Chapter 6 on gas transport details the key information to score well on this question
Answers should have included a description of the need for a pressure gradient for flow and a discussion on right atrial pressure, mean systemic filling pressure and resistance to blood flow. The discussion of each of these factors included definitions, normal values, factors affecting them and the direction of change on venous return. Diagrams were not essential, but their use assisted some candidates in explaining the effects of RAP on venous return.
Describe protein binding and its significance in pharmacology.
Example answer
Protein binding
Drugs in blood can exist in two forms (protein bound, protein unbound)
Protein binding of drugs involves the formation of reversible drug-protein complexes
Protein + drug <-> protein-drug complex
Drugs vary greatly in degree of plasma protein binding
e.g. warfarin and phenytoin which are >95% protein bound
e.g. rocuronium which is approx. 10% protein bound
Types of proteins
Drugs can bind to proteins in the plasma (e.g. albumin, globulins) or tissue
Albumin is the most sig. drug binder and binds neutral/acidic drugs (e.g. barbiturates)
a-1 glycoproteins and globulins bind basic drugs (e.g. morphine)
Haemoglobin can bind some drugs e.g. phenytoin
Effect of protein binding
Only unbound fraction exerts can interact with receptors and exert its pharmacologic effect
Only unbound drug in plasma can freely cross cell membranes
Only unbound drugs can undergo filtration or metabolism
For drugs which are highly protein bound (>90%), small changes in degree of protein binding can have sig. clinical effects. I.e. protein binding from 99% to 98% doubles to unbound (active) drug concentration (from 1% to 2%)
Highly tissue bound drugs have long duration of action, high volume of distribution and readily build up in the body
Protein binding is affected by
Protein factors
Concentration of protein (decreased protein > increased unbound drug)
Number of available protein binding sites
Drug factors
Protein affinity
Concentration of drug - higher drug concentration > saturation of protein > higher unbound (free) drug
Patient factors
temperature and pH
Inflammation, infection, surgery > increased acute phase reactants > increased protein binding
Age
Examiner comments
19% of candidates passed this question.
Descriptions of protein binding were generally too brief (e.g. a statement saying that drugs and hormones bind to proteins in the plasma rather than a description of usually reversible binding with a drug-protein equilibrium). It was expected that the factors which determine protein binding would be described. Marks were attributed if proteins, along with characteristics of the drugs they bind, were named. Candidates achieved better marks if they named the pharmacological parameters affected by protein binding and explained how and why change occurs along with the significance of those changes. Few candidates differentiated between tissue and plasma protein binding and the different effects on the volume of distribution.
secretin (stimulated by low duodenal pH) > decreased emptying
Cholecystokinin (stimulated by fatty acids) > decreased emptying
Somatostatin > decreased emptying
Gastrin (stimulated by stretch, amino acid content) > increased emptying)
Motilin: stimulates migrating motor complex > increased emptying
Drugs factors
e.g. opioids > decreased empyting
eg. metoclopramide > increased emptying
Examiner comments
24% of candidates passed this question.
Candidates were required to provide a description of gastric emptying (40% marks). Although
the question showed the allocation of marks, many candidates did not provide sufficient detail
for this section. This required some description of what gastric emptying is (the co-ordinated
emptying of chyme from the stomach into the duodenum).
Better answers provided detail regarding the process of gastric emptying in the fed and fasted
state and differentiated between liquids, solids, carbohydrate, protein and fats. Factors
regulating emptying included an outline of peristaltic waves, the basal electrical rhythm and its
modulation, the migratory motor complex (MMC) and its modulation, neural input, stretch and
hormonal control.
Many candidates erred by answering the question "the regulation of gastric secretions" rather
than the question (the regulation of gastric emptying). Although they scored well for hormonal
control, they missed out on marks for the other factors relevant to the regulation of gastric
emptying.
Describe the renal handling of water including the modulation of water excretion
Example answer
Renal handling of water
Glomerulus
Water is freely filtered at the glomerulus (~180L / day)
The amount filtered will depend on the GFR and starlings forces
Proximal convoluted tubule (PCT)
Approximately 60-70% of the filtered water is reabsorbed
Secondary active transport of Na in the PCT creates an osmotic gradient which allows passive absorption of water via osmosis
Loop of Henle (LOH)
Approximately 10-15% of the filtered water is reabsorbed in the descending LOH
Iso-osmotic absorption due to the increased medullary concentration gradient
The ascending LOH is relatively water impermeable
Distal convoluted tubule (DCT)
Approximately 0-5% water reabsorbed in DCT
Relatively impermeable
Collecting duct (CD)
Reabsorbs 5-20% of the remaining water (depending on the level of ADH)
ADH inserts luminal aquaporins in collecting duct cells which allows increased reabsorption of water down the osmotic concentration gradient
Regulation
There is an obligatory water loss of ~500mls a day needed for waste clearance
The body also needs to maintain fluid and osmolality homeostasis
The main site of water regulation in the nephron is in the collecting ducts via the action of ADH
Mechanism
Primary:
Osmoreceptors in hypothalamus detect increased osmolality > increased production of ADH > increased release of ADH from posterior pituitary > increased luminal aquaporins in CD > increased water reabsorption
ANP/BNP secretion is reduced with decreased BP (stretch) > decreased GFR + activation of RAAS
Examiner comments
37% of candidates passed this question.
This question required a brief introduction of the role the kidney plays in water balance; a more
detailed description of how water is handled as it passes through the various segments of the nephron (glomerulus, PCT, Loop of Henle, DCT and Collecting Duct); the modulation of water excretion by the kidney due to ADH (vasopressin) and how this operates; and the stimuli (osmotic and non-osmotic) for ADH secretion. Although worth mentioning in the context of the effect they have on water movement through the kidney, detailed explanations of Starling's forces in the glomerulus, and of the operation and maintenance of the counter-current mechanism, were not required. More important was describing the control of water reabsorption in the collecting ducts (and thus modulation of water excretion by the kidney) under the influence of ADH
PO bioavailability <1%. Only given orally for C. diff infections.
PO bioavailability 70%
Distribution
Poor CSF penetration (requires higher dosing)
VOD = 0.5L / kg
50% protein bound
95% protein bound
VOD = 0.3 L /kg
CNS penetration with meningitis only
Metabolism
No metabolism
Hepatic metabolism
Elimination
Unchanged in the urine
T 1/2 = 6 hrs
Renal elimination (predominately unchanged)
T 1/2 = 1 hour
Monitoring
Renal function
Monitor LFTs, renal function
Resistance
Cannot treat VRE (VanA/B resistance genes)
Can treat b-lactamase producing bacteria, but not MRSA (mecA gene)
Examiner comments
49% of candidates passed this question.
Most candidates structured their answers well. Expected information included: the class of antibiotic of each agent, their respective pharmaceutics, pharmacodynamics, pharmacokinetics, indications and adverse effects. Better answers provided pharmacodynamic and pharmacokinetic information relevant to each drug rather than generic statements. Good answers also included the common resistance mechanisms for both agents.
Describe the anatomy relevant to the insertion of an intercostal catheter.
Example answer
Surface anatomy
Lateral approach
ICC is inserted in the 'triangle of safety' based off surface landmarks
Anterior border: lateral border of the pectoralis major
Posterior Border: lateral border of latissimus dorsi
Inferior border: 5th intercostal space
Superior: base of axilla
Anterior approach
Second intercostal space, midclavicular line
Layers of dissection / path of needle
Skin
Subcutaneous tissue
Pectoralis muscle (in anterior approach only)
External intercostal muscle
Internal and innermost intercostal muscles
Parietal pleura
Pleural space
Important anatomical considerations
Intercostal neurovascular bundle
Sits in the inferior aspect of the rib, between innermost and internal IC muscles
Vein > artery > nerve (from superior to inferior)
Care to avoid this by aiming for the rib below, and guiding over the top of the inferior rib
Anterior approach
Variable degrees of breast/subcutaneous tissue
Will also contain the pectoralis major muscle (variable thickness) between subcutaneous tissue and intercostal muscles
5th intercostal space
The reason it is important to place above the 5th intercostal space as this reduces of inadvertently placing the ICC into intrabdominal structures (e.g. liver, spleen) or penetration of the diaphragm (as the diaphragm can go as high as 5th intercostal space during expiration / pregnancy)
Deeper structures
Beneath pleural space is the visceral pleura and lung parenchyma, which should be avoided..obviously
Internal mammary artery / lymphatic ducts
Too far medial on anterior approach risks damage to these structures
Examiner comments
56% of candidates passed this question.
An anatomy question expects the use of anatomical nomenclature to describe relationships. Good answers defined the “safe triangle†for the lateral approach, soft-tissue layers passed through from skin to pleura and relationship of the neurovascular bundle to the ribs and intercostal muscles. Additional marks were gained for describing the anterior approach and related structures. Common omissions included description of deeper structures (relations) including intrathoracic and intra-abdominal organs and level of the diaphragm with regard to rib space. No marks were awarded for a description of intercostal catheter insertion.
Regulation of BGL is via short and long term mechanisms
Insulin and glucagon are the main regulatory hormones
High BGL
Increased BGL (>6.0mmols) is sensed directly by the pancreas
The increased glucose is taken up by GLUT receptors > undergoes glycolysis > increased ATP/ADP ratio > depolarisation > exocytosis of insulin from pancreatic B-islet cells
There is an initial rapid release, followed by a prolonged slow release
The increased insulin results in
Increased glucose uptake into cells and Glycogenesis (liver)
Decreased gluconeogenesis, glycogenolysis and lipolysis
The net effect is reduced BGL
Low BGL
Decreased BGL (or during times of fasting) is sensed by pancreas
Leads to
Increased glucagon secretion from a-islet cells in pancreas (<3.0 mmols)
Decreased insulin secretion from the B-islet cells in pancreas (<4.0 mmols)
Glucagon acts via GPCR (Gs) to
Increased glycogenolysis and gluconeogenesis in the liver
Increased lipolysis and ketoacid formation
Hypoglycaemia also directly stimulates the hypothalamus (with prolonged hypoglycaemia, starvation)
Stimulates TRH release > increased TSH > increased GIT absorption of glucose
Stimulates "hunger" centre in the lateral hypothalamus > seek food
Direct SNS stimulation of adrenal medulla > increased adrenaline > increased catabolism
The net effect is increased BGL
Other factors
BGL control is interconnected to liver function
Involved in glycogenolysis/glycogenesis functions regulated by insulin/glucagon
Hence liver dysfunction can impair its glucostat function and BSL control
BGL control is interconnected to renal function
Can help modulate BGL control through control of absorption of glucose
Other
Insulin and glucagon also affected by: cholecystokinin, somatostatin, food intake
Examiner comments
53% of candidates passed this question.
A definition of normal glucose levels was expected, mentioning how it is regulated despite variable intake. Most answers incorporated the roles of insulin/glucagon and the glucostat function of the liver. Sufficient detail regarding the mechanism of insulin release was often lacking. Extra marks were awarded for description of the role of the satiety centre in the hypothalamus, glucokinase and processes in fasting and starvation that maintain blood glucose levels. Marks were not awarded for describing effects of insulin and glucagon unrelated to glucose control.
Histamine release: none ANS: no vagolysis OTHER: anaphylaxis (very rare)
Pharmacokinetics
Onset
Onset: 45-90s Duration: ~30 mins
Onset: 1-3 minutes Duration: 30-45 minutes
Absorption
IV only
IV only
Distribution
VOD = 0.2 L /kg Protein binding = 10% Doesn't cross BBB
VOD = 0.15 L/kg Protein binding = 15%
Metabolism
Minimal hepatic metabolism (<5%)
Organ independent Hoffman elimination (70-90%) > laudanosine and acrylate
Elimination
Bile 70%, Renal 30% elimination Unchanged drug T 1/2 = 90 mins
Renal and biliary elimination (10-30%) Inactive metabolites T 1/2 - 30 mins
Special points
Reversible with sugammadex
Not reversible with sugammadex
Examiner comments
32% of candidates passed this question.
This question was best answered using a tabular format outlining class of drug, pharmaceutics, pharmacokinetics, reversibility and side effects. Better answers commented on the significance of the differences between the two agents and its relevance to ICU practice. Many candidates confused these muscle relaxants with each other and with depolarising muscle relaxants.
Increased minute ventilation (hyperbolic relationship with rapidly increasing MV when PaO2 <50-60)
Cardiovascular response
Hypoxic vasoconstriction of pulmonary circulation
Hypoxic vasodilation of systemic circulation
Autonomic response
Relative increase in sympathetic tone
Leads to tachycardia, increased CO, increased SVR
BP stable / slight increase
Metabolic changes
If concurrent hypoxia there will be a switch from aerobic to anaerobic metabolism
Hypoxia inducible factors (HIF)
With tissue hypoxia, hypoxia inducible transcription factors are no longer broken down.
HIFs > increased erythropoiesis (increased EPO), cell differentiation and angiogenesis
Examiner comments
34% of candidates passed this question.
A logical approach to answering this question included a definition of hypoxaemia and then a
discussion of the sensors, integrators and effectors involved. It was expected that candidates
would cover the peripheral chemoreceptor response (including the respiratory, cardiovascular
and autonomic effects), time course of the ventilatory response, hypoxia-inducible factors,
vascular effects (hypoxic vasoconstriction in the pulmonary circulation and vasodilatation in the
systemic circulation) and metabolic changes (switch to anaerobic metabolism). No marks were
awarded for discussing the causes of hypoxaemia. Many candidates incorrectly stated that
hypoxaemia is detected by the central chemoreceptors.
Outline the production / absorption (30% of marks), composition (30% of marks) and function of cerebrospinal fluid (CSF) (40% of marks).
Example answer
CSF
ECF located in the ventricles and subarachnoid space
~2ml/kg of CSF
Divided evenly between the cranium and spinal column
Production
Constantly produced
~550ml produced per day (~24mls/hr)
Produced by
Choroid plexus (70%) - located in ventricles of brain
Capillary endothelial cells (30%)
Produced by a combination of ultrafiltration (via fenestrated choroidal capillaries) and active secretion
Na actively transported out. Gradient drives co-transport of HCO3 + Cl
Glucose via facilitated diffusion, water by osmosis
Composition relative to plasma
Similar: Na, osmolality, HCO3
Increased: Cl, Mg, CO2
Decreased: pretty much everything else (protein, potassium, calcium, glucose, pH)
Circulation
Circulation is driven by
Ciliary movement of ependymal cells
Respiratory oscillations and arterial pulsations
Constant production and absorption
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
Rate of ~24mls/hr
By the arachnoid villi
Located predominately in the dural walls of the sagittal + sigmoid sinuses
Function as one way valves, with driving pressure leading to absorption.
Functions
Mechanical protection
The low specific gravity of CSF > decreased effective weight of the brain (1500g > 50g)
With the reduced weight
Less inertia = less acceleration/deceleration forces
Suspended > no contact with the rigid skull base
Buffering of ICP
CSF can be displaced / reabsorbed to offset any increase in ICP
Stable extracellular environment
Provides a constant, tightly controlled, ionic environment for normal neuronal activity
Control of respiration
The pH of CSF is important in the control of respiration (CO2 freely diffuses into CSF and can activate central chemoreceptors)
Nutrition
Provides a supply of oxygen, sugars, amino acids to supply the brain
Examiner comments
71% of candidates passed this question.
This question was generally well answered. Better answers noted production including an
amount, site and mechanism. Similarly, absorption included the site, the rate and factors which
affect the rate. The electrolyte and pH and how they compare to extracellular fluid should have
been included in the section on composition.
Accounts for membrane permeability and surface area
Delta = reflection constant
Takes into consideration protein leakage
Values range from 0-1
Capillary hydrostatic pressure (Pc)
Main factor determining bulk flow under physiological conditions
Normally ~35mmhg at arterial end, 15mmHg at venous end of capillary.
Determined by
The ratio of resistances between pre/post capillary arterioles
Arterial and venous blood pressure and gravity
Interstitial hydrostatic pressure(Pif)
Normally ~0mmhg (there is minimal interstitial fluid which is draining away)
Affected by anything that modifies lymphatic drainage (e.g. immobility, tourniquet)
Plasma oncotic pressure (Ï€p)
The osmotic pressure attributed to by large insoluble proteins (e.g. albumin) within plasma
Normally ~28mmHg. Does not rapidly change
Affected by plasma protein concentrations and intravascular fluid status
Interstitial oncotic pressure (Ï€if)
Osmotic pressure attributed to by small amounts of insoluble proteins which have leaked into interstitial space
Normally ~3mmHg. Does not rapidly change
Affected by membrane integrity
Using the above values at venous/arterial ends, it is demonstrated that bulk flow occurs
OUT of the vessel at arterial end
IN to the vessel at venous end
Main factor as described is the Capillary hydrostatic pressure gradient (Pc - Pif)
Examiner comments
57% of candidates passed this question.
The expected answer included a clear explanation of Starling’s forces, including an understanding of the importance of the relative difference along the length of the capillary, with approximate values and examples of factors that influence them. Some explanation of what contributed to the hydrostatic or osmotic pressure gained more marks than merely stating there was a pressure. Several candidates digressed to Fick’s law of diffusion or intracellular flow of ions which was not directly relevant to capillary flow.
Describe ketone bodies including their synthesis and metabolism
Example answer
Ketone Bodies
Water soluble molecules, derived from fatty acids, that contain ketone groups
Three main compounds: acetoacetate, 3-β-Hydroxybutyrate, and acetone
Normal plasma level is <0.6mmol/L
Ketogenesis
Ketone bodies can only be produced in the liver
β-oxidation of fatty acids in the liver produces acetyl-CoA
Acetyl-CoA usually enters the citric acid cycle to produce ATP
When large amounts of acetyl CoA are produced they condense to form acetoacetate
Acetoacetate is then reduced in the mitochondria to 3-β-hydroxybutyrate (majority) or acetone (minority).
Regulation
The body constantly produces small amounts of ketone bodies (even during fed states)
When carbohydrate stores are available the main pathway for energy utilisation is glycogenolysis
Ketogenesis is accelerated by decreased insulin levels and increased glucagon levels (e.g. in times of starvation or carbohydrate restriction). This leads to increased activity of hormone sensitive lipase and acetyl Coa Carboxlyase which drive ketogensis
As the lack of insulin is the main driver of ketogenesis, it explains why Type 1 diabetics develop diabetic ketoacidosis
Metabolism/utilisation
Ketone bodies can be used as an energy substrate by
Kidney, skeletal muscle and cardiac muscle cells (under physiological conditions)
Nervous tissue (during times of starvation)
Process
Ketone bodies enter mitochondria
Ketone body reconstituted to Aceto-acetyl CoA (by SCOT)
Cleavage of acetyl group by MAT to form Acetyl CoA
Acetyl CoA enters the Citric acid cycle
Examiner comments
35% of candidates passed this question.
Whilst most candidates understood that ketones provided an alternative source of substrate for energy production, many lacked a basic understanding of their synthesis and metabolism Important facts included what ketone bodies are, where they were synthesised, where they were taken up and used as fuel, under what circumstances they are used and the integral role of insulin. Many candidates accurately reproduced the glycolytic and/or the TCA cycle, but this was not being examined, and did not score additional marks. Many candidates incorrectly stated that ketone production was the result of anaerobic metabolism.
E.g. B agonists --> increased chronotropy and inotropy
Electrolytes
E.g. Calcium: too little = impaired systolic function, too much = impaired diastolic function
Factors affecting LV diastolic function
LV diastolic function is determined by it compliance
LV systolic function
Poor LV systolic function > high end systolic volume > impedes diastolic filling
Heart rate
Increased HR > shorter time in diastole > reduced compliance; filling is time dependant
Lusitropic properties of the ventricle
Increased by SNS tone and catecholamines
Wall thickness
Increased thickness = reduced compliance
Examiner comments
12% of candidates passed this question.
Candidates often misinterpreted the question and described determinants of cardiac output. The answer should have focussed on factors affecting/contributing to normal LV function - not pathological states. Some answers showed a lack of appreciation that normal left ventricular function is afterload independent, due to compensatory reflexes. Answers needed to consider intrinsic and extrinsic factors affecting LV function - the latter (e.g. SNS, PSNS, hormones, drugs) was often left out. Answers needed to consider both systolic and diastolic function. An excellent answer included physiological phenomena such as the Treppe effect, Anrep effect and baroreceptor and chemoreceptor reflexes. Mention of normal conduction and pacing as well as blood supply limited by diastole scored additional marks.
Drug interactions: displacement from protein binding sites by highly protein bound drugs e.g. phenytoin > increased unbound fraction > increased risk of toxicity
Management of local anaesthetic toxicity
Alkalinise
Decreases the unbound (active) fraction of the drug
Give intralipid
Increases the lipid bound fraction (decreases active unbound fraction)
Examiner comments
28% of candidates passed this question.
Most questions lacked a systematic approach to the question and specific detail. The relationship between systemic toxicity (CNS and CVS) and plasma levels should be described. Many candidates did not clearly state that CNS toxicity occurs at lower plasma levels that CVS toxicity. Factors that affect toxicity (e.g. drug factors, patient factors, interactions) needed to be elaborated with some detail. Patient factors such as age, pregnancy, acidosis, hyperkalaemia, hepatic failure were often omitted. Finally, marks were also awarded for noting methaemoglobinaemia as possible toxicity and the existence of specific therapy (intralipid).
Better answers were tabulated and included sections on pharmaceutics, indications and an explanation on how the difference in molecular weight influenced pharmacodynamics and pharmacokinetics. Knowledge of adverse effects was limited to bleeding and HITTS, often without consideration of relative risk from LMWH. Many candidates did not know the t1/2 of UFH or LMWH.
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
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>
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 Henry’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.
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.
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
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. Fowler’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.
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.
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).
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 drugs’ context-sensitive half-times should have included the differences in re-distribution into other compartments and rates of elimination.
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.
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.
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
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.
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.
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)
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.
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.
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.
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
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.
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)
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.
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.
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
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 ‘Level A’ 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 ‘moderate, good and some’ are vague and should be avoided. Only correct numerical values (or ranges) attracted full marks.
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
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 ‘effective’ 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 – both were accepted.
No candidate correctly pointed out the fluids respectively have 9g NaCl and 50g dextrose per litre.
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.
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.
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.
Compare and contrast the pharmacology of ibuprofen and paracetamol.
Example answer
Examiner comments
65% of candidates passed this question.
This was a standard compare and contrast question of common analgesic pharmacology and it
was generally well answered. The use of a table ensured all areas were covered including
class, indications, pharmaceutics, mode of action, pharmacodynamics, pharmacokinetics and
adverse effects. The uncertain nature (and possibilities) of the mechanism of action of
paracetamol was alluded to in better responses.
Details of the comparative pharmacokinetics were often lacking. Answers should have included
a comment on first-pass effect, the significance of the difference in protein binding and the
details of metabolism, particularly paracetamol. Metabolism limited to "hepatic metabolism and
renal excretion†gained no marks as better responses were more detailed and clearer about the
differences between the two drugs. Knowledge of metabolism at therapeutic doses and the
effect of overdose were expected. Better answers included potential interactions with other
drugs (e.g. warfarin) and contraindications to the use of these drugs.
Outline the daily nutritional requirements, including electrolytes, for a normal 70 kg adult.
Example answer
Examiner comments
21% of candidates passed this question
The provision of nutrition is a core skill in ICU. An understanding of its key elements enables prescription and modification. However, most answers lacked detailed information which is available in the standard texts. Better responses outlined the caloric requirements including each major element (water, carbohydrate, fat and protein) along with the caloric values and potential sources. Essential amino acids, fatty acids, fat and water-soluble vitamins were expected. A list of the requirements for major electrolytes and some of the trace elements were expected. Some candidates seemed to confuse calories, kilocalories and kilojoules.
Some answers did not provide the nutritional requirements, as asked, but instead discussed the
fate of the nutrients; hence did not score marks. Candidates are reminded to read the question
carefully.
Describe the factors that determine the filtered load of a substance at the renal glomerulus.
Example answer
Examiner comments
67% of candidates passed this question
A good place to start was with the correct equation for a filtered load and a description of the
components. Better answers described the components and how they differ and change over
the glomerulus. Many candidates usefully based answers around the Starling forces.
A summary of factors including the role of plasma concentration, protein binding, molecular size
and charge was required to pass. Many answers gave examples for the effects of size and
charge and relate endocrine responses to specific alterations in arteriolar tone and how this
affected filtration. A detailed discussion of cardiovascular and endocrine responses to
hypovolaemia was not required.
Some candidates confused clearance with filtered load. Candidates are reminded to write
legibly - especially where subscripts and Greek letters are used. Directional arrows (if used)
should correlate with text.
Describe how interstitial fluid recirculates to the vascular system.
Example answer
Examiner comments
10% of candidates passed this question
Candidates had a limited understanding of this area of the syllabus. It was expected that answers would describe important concepts including the anatomy of venous structures, valves and lymphatics, permeability and factors which influence permeability. A description of hydrostatic forces, other pressures involved, and the role of osmotic and electric forces were required.
This question was generally well answered and lent itself well to a tabular format. Expected information included an approximation of the molecular weights / significance of the differences in size and therefore its mechanism of action. Other pertinent areas to mention included pharmacokinetic differences and its use in renal failure, side effect profiles, monitoring, predictability of response and reversibility for the two agents.
Describe the effects of Ventilation/Perfusion (V/Q) inequality on the partial pressure of oxygen (PaO2) in arterial blood.
Example answer
Examiner comments
48% of candidates passed this question
Overall answers lacked sufficient detail on a core area of respiratory physiology. Answers expected included a description of V/Q ratios throughout the lungs and an explanation of how V/Q inequality lowers PaO2.
Compare and contrast the sympathetic and parasympathetic nervous systems.
Example answer
Examiner comments
75% of candidates passed this question
This question was generally well answered A table or diagram lent structure to the answer. More complete answers included details on the function, anatomy, a description of the pre- and post-ganglionic fibres, ganglia, receptors and neurotransmitters involved.
Whilst most commented on ‘fight or flight’ for the SNS and ‘rest and digest’ for the PNS, no candidate observed that the SNS is a diffuse physiological accelerator and that the PNS acts as a local brake. No candidate included the fact that the SNS supplies viscera and skin whilst the PNS only supplies the viscera. Many candidates failed to make reference to the fact that the postganglionic SNS receptor is G protein coupled and the PNS postganglionic receptor is Gcoupled on muscarinic receptors but operates an ion channel when nicotinic.
Candidates may have scored higher if they had provided a little more detail in their answers.
Classify calcium channel antagonists and give one example of each class (30% of marks). Describe the pharmacology of Nimodipine including important drug interactions (70% of marks).
Example answer
Examiner comments
19% of candidates passed this question
The classification was done well. Most candidates demonstrated that they had a structure for a “drug†question, but were often challenged to fill in the detail of that structure and failed to deliver enough content to secure a pass. Many candidates wrote a generic answer for calcium channel blockers instead of the specifics of nimodipine.
Frequently the pharmacokinetic data recounted was incorrect. Candidates failed to distinguish between absorption and bioavailability. The difference between oral and intravenous dosing was often omitted. Few answered the section on important drug interactions.
Briefly outline the formation, absorption, distribution, role and composition of cerebrospinal fluid
Example answer
Examiner comments
44% of candidates passed this question
The question spelt out very specific areas of CSF physiology to outline and the marks were evenly distributed among these areas. The candidates who did not pass this question usually did not provide enough detailed information. Details of the production and absorption of CSF were commonly lacking. The majority of candidates correctly described the composition of CSF; indicating whether a particular variable was higher or lower than in plasma, scored less marks than more specific information.
Compare and contrast two methods of measuring cardiac output.
Example answer
Examiner comments
35% of candidates passed this question
Good answers began with a definition of cardiac output. For each method, it was expected that
candidates discuss the theoretical basis, equipment, advantages and disadvantages / sources
of error and limitations. Additional marks were awarded when an attempt was made to compare
and contrast the two methods (often helped by the use of a table).
A structured approach proved a good basis to answer this question. It was expected candidates
would outline the uses such as anaesthesia, more prolonged sedation or possible additional roles in patients with seizures or head injuries. Discussion of the presentation and pharmaceutics, including a comment on antibacterial preservatives or lack thereof was expected. The mechanism of action should have been described. It was expected candidates could provide an indication of the usual dose (and how it differs in the more unwell / elderly patient population). A maximal rate and possible toxicity was expected.
A discussion on the pharmacodynamics by major organ systems was expected and credit was given for additional comments about hyperlipidaemia, urine colour changes or metabolic alterations. It was expected that candidates would mention propofol infusion syndrome at some point in their answer with some mention of clinical features or pathophysiology.
The important aspects of its pharmacokinetics should have been mentioned (high protein binding, large volume of distribution, termination of effect by redistribution, hepatic metabolism, context sensitive half life). A mention of adverse effects would complete the answer.
Both of these commonly used agents are level A in the syllabus and thus a high level of detail was expected. Marks were awarded in the following areas - pharmaceutics, mechanism of action, pharmacokinetics (PK) and side effects. For the PK parameters a general description rather than exact values was sufficient (i.e. ‘high protein binding’ rather than ‘98% protein bound’). It was expected that candidates would mention the fact that clopidogrel is a pro-drug and the factors which influence its conversion to the active form. Additional marks were awarded for well-structured answers which attempted a comparison between the two drugs (helped by the use of a table).
Compare and contrast the pharmacology of intravenous fentanyl and morphine
Example answer
Examiner comments
68% of candidates passed this question
Good candidates produced a well-structured answer and highlighted the differences between the two drugs. It was important to include the dose, potency, time course of effect of both agents, and differences in pharmacokinetic and pharmacodynamic effects. Candidates should have specific knowledge of these important drugs. Many candidates failed to focus the question on intravenous fentanyl and intravenous morphine as asked. No marks were given for information about other routes of administration.
Explain the mechanisms responsible for the cell resting membrane potential (60% of marks) and describe the Gibbs Donnan effect (40% of marks)
Example answer
Examiner comments
35% of candidates passed this question.
A good answer included a definition of the resting membrane potential and a clear description of
the factors that determine it. Explanation of these factors should have included a detailed description of the selective permeability of the membrane, electrochemical gradients and active transport mechanisms. Answers should demonstrate awareness of the Nernst equation and the Goldman-Hodgkin-Katz equation. These were often confused, sometimes with the GibbsDonnan effect. Descriptions of the Gibbs-Donnan effect generally lacked detail and understanding. The better answers included a definition and discussed in detail the influence of non-diffusible ions (intracellular proteins) on the distribution of diffusible ions
List the properties of an ideal inotrope (50% of marks). How does adrenaline compare to these ideal properties (50% of marks)?
Example answer
Examiner comments
98% of candidates passed this question
Many candidates scored very highly on this core topic. It was expected information be included
on pharmaceutics, cost, availability and compatibilities. Relevant pharmacokinetics (onset/offset, titratability) and pharmacodynamics (including relevant receptors, nuances of haemodynamic effects e.g. effect on diastolic pressure and regional perfusion) should have been detailed. Adverse effects and safety profile (e.g. use in pregnancy, therapeutic index) should also have been included. Good answers were structured and highlighted differences with specific facts and data
Related to the pharmacological action of the drug (dose related)
- Common
- Predictable
- Low mortality
- Bleeding related to administration of anticoagulants (e.g. heparin)
Reduce or withhold
Type B
'Bizarre'
Non-dose related (any exposure > reaction)
- Rare
- Unpredictable
- Not related to action of drug
- High mortality
Anaphylaxis to penicillin's
Withhold and avoid future use
Type C
'Chronic'
Due to the cumulative dose received (dose and time related)
- Uncommon
Adrenal suppression with prolonged course of corticosteroids.
Reduce or withhold (may need to happen over time)
Type D
'Delayed'
Does not appear for a prolonged period after exposure (time related)
- Uncommon
- Usually also dose related
Tardive dyskinesia from long term use of typical antipsychotics
Can be intractable
Type E
'End of treatment'
Withdrawal reactions from drug cessation
- Uncommon
- Fast onset
Seizures from abrupt withdrawal of benzodiazepines or alcohol
Reintroduce + withdraw slowly
Type F
'Failure'
Unexpected failure or decrease in efficacy
- Common
- Dose related
Ineffectiveness of clopidogrel (non metabolisers)
Increase dosage / alternative therapy
Examiner comments
44% of candidates passed this question.
Candidates should have provided a definition of adverse drug reactions and then a classification. There are at least two widely accepted systems for classification, either was acceptable; though candidates often switched between both which led to a less structured answer. The WHO classification is comprehensive and logical, though both Rang and Dale and Goodman and Gilman also have sections on this topic. Common errors were the citing of examples with the incorrect mechanism, describing only drug interactions rather than all adverse reactions and focussing the answer on the 4 hypersensitivity reactions which could only score a low mark. Some candidates confused drug errors with adverse reactions
Define and explain damping, resonance, critical damping and optimum damping.
Example answer
Examiner comments
25% of candidates passed this question
Concise definitions were required with a clear explanation of the underlying physical principles.
The response time of the system, degree of overshoot, effect on amplitude, noise and ability to
faithfully reproduce frequencies relative to the natural resonant frequency were important considerations.
Many candidates interpreted the question as relating to arterial lines and a detailed discussion
of the components and characteristics of an intra-arterial catheter and transducer system did not
attract marks.
Draw and numerically label, on a spirogram, the lung volumes and capacities of a 30 kg child.
Example answer
Examiner comments
87% of candidates passed this question.
This core respiratory physiology topic was well answered by most candidates. Candidates generally were able to draw a spirogram. A common omission was inspiratory capacity.
Generally, there was a lack of knowledge about this topic with many candidates confusing vasovagal syncope with a Valsalva or orthostatic hypotension. A “vasovagal†is from excessive autonomic reflex activity in contrast to orthostatic hypotension which is a failure of the autonomic reflex response.
A good place to start was with a description of vasovagal syncope, also known as neurocardiogenic syncope. It is benign, self-limiting and caused by an abnormal or exaggerated autonomic response to various stimuli (which should have been listed). The mechanism should have been described including the various receptors involved
Describe and compare the action potentials from cardiac ventricular muscle and the sinoatrial node.
Example answer
Examiner comments
95% of candidates passed this question
This topic was well understood and answered by most candidates. Some candidates had a good knowledge base but missed out on potential marks by failing to compare and contrast. A diagram outlining the various phases was a useful way to approach the question.
Define bioavailability. Outline the factors which affect it.
Example answer
Examiner comments
33% of candidates passed this question
Many candidates did not specify that bioavailability describes the proportion/fraction of drug
reaching the systemic circulation (to differentiate from the portal circulation). Some candidates considered only factors impacting absorption from the GI tract or stated that bioavailability related only to orally administered drugs. Candidates failed to provide an equation, or got equations or graphs wrong. Nearly all candidates failed to provide a comprehensive list of factors affecting bioavailability.
Outline the anatomy of the internal jugular vein relevant to central venous line cannulation (80% of marks). Include important anatomical variations (20% of marks).
Example answer
Internal jugular vein
Originates at the jugular bulb (confluence of the inferior petrosal and sigmoid sinus')
Exits skull via the jugular foramen with CN IX, X, XI
Descends inferolaterally in the carotid sheath (initially posterior > lateral to carotid artery with descent)
Terminates behind the sternal end of the clavicle where it joins with the subclavian vein to form the brachiocephalic vein
Variation in relation to carotid (e.g. anterior) in up to 1/4 cases
Ultrasound anatomy
Often lateral to carotid (not always) and often larger than carotid
Unlike carotid: Non pulsatile, thin walled, compressible
Doppler flows can also be helpful.
Surface anatomy
Identify triangle between the clavicle and two heads of SCM
Palpate carotid
Puncture lateral to carotid artery at 30 degree angle
Aim caudally towards ipsilateral nipple
Examiner comments
14% of candidates passed this question.
Good answers were structured including origin, termination, tributaries, relationships, surface
anatomy and common variations.
Factual inaccuracies were common and there was confusion about the relations of the internal
jugular vein. Many candidates did not mention the changing relationship between the internal
jugular and the carotid artery as they travel through the neck or the changes that result from
repositioning for insertion. Many candidates also forgot to mention surface anatomy and a
number talked about ultrasound and views used for insertion of central lines. Common
omissions included the origin, tributaries, relationship with the correct cranial nerves and the fact
that it is usually larger on the right. Almost nobody mentioned the relationship to the pleura.
What is functional residual capacity (30% of marks)? Describe two methods of measuring functional residual capacity (70% of marks).
Example answer
Examiner comments
59% of candidates passed this question
Most candidates could state 2 methods of measuring FRC. Some candidates (especially for
nitrogen wash out) failed to provide enough information e.g. statements such as "if the amount
of nitrogen is measured then FRC can be derived" were insufficient to score many marks.
Outline the anatomy and physiology of the parasympathetic nervous system.
Example answer
PSNS
Division of the autonomic nervous system
Important for physiological regulation of our organ systems
Broadly speaking, there are pre + post ganglionic neurons
Preganglionic neurons
CN 3,7,9,10, as well as S2-4 (craniosacral outflow)
Long and synapse close to the effector organ
Neurotransmitter is ACh > nicotinic receptor
Postganglionic neurons
Short
Neurotransmitter is ACh > muscarinic receptor
Anatomy + effects (based on "target" organ system)
Target Organ
Pre- Ganglionic fibre origin
Pre- Ganglionic nerve
Ganglion
Post- Ganglionic Receptor
Effect
Heart
Vagal nucleus in Medulla
CN X
Cardiac plexus ganglia
M2
Decreased inotropy and chronotropy
Lung
Vagal nucleus in Medulla
CN X
Pulmonary plexus ganglia
M3
Bronchoconstriction
Pupils
Oculomotor nucleus
CN III
Ciliary ganglion
M3
Constriction
Salivary glands
Superior and inferior salivary nuclei
CN VII (mandibular, maxillary)
CN IX (parotid)
-Submaxillary ganglion
- Otic ganglion
M3
Salivation
GIT
Vagal nucleus
Spinal cord
CN X
S2,3,4 nerves
Gastric and hypogastric plexus
M3
Increased peristalsis
Bladder, Penis
Spinal cord
S2,3,4 nerves
Hypogastric plexus
M3
Contraction of bladder, erection
Adrenal gland
-
-
-
-
No effect
Arterioles
-
-
-
-
No effect
Sweat gland
-
-
-
-
No effect
Examiner comments
32% of candidates passed this question
An efficient way to answer this question was to describe the anatomy and physiology of both cranial and sacral sections together. High scoring answers included an outline of the relevant nerves, the various ganglia, neurotransmitters and physiological effects. Some candidates described the cellular basis of Nicotinic, Muscarinic and M1-M5 receptors which didn't attract marks.
Outline the components of dietary fat (20% of marks). Describe their possible metabolic fates (80% of marks).
Example answer
Examiner comments
21% of candidates passed this question
Almost all candidates interpreted "metabolic fate" to mean absorption, digestion and transport of
fat. Hence a lot of time was spent on this and little on the fate of fat once it enters the blood stream. The processes of neither beta oxidation, nor lipogenesis were not well understood. Ketone body production was better understood.
Classify and describe the mechanisms of drug interactions with examples
Example answer
Classification of drug-drug interactions
Example
BEHAVIOURAL
- One drug alters behaviour of patient for another
- A depressed patient taking an antidepressant may be more compliant with other medications for unrelated conditions
PHARMACEUTIC
- Formulation of one drug is altered by another before administration
- Precipitation of thiopentone (basic) and vecuronium (acidic) in a giving set
PHARMACOKINETIC
Absorption
Bioavailability of bisphosphonates is reduced when co-administered with calcium as the drugs interact to form insoluble complexes
Distribution
Valproate and phenytoin compete for the same transport protein binding sites > decreased protein binding phenytoin > increased effect
Metabolism
Macrolides reduce metabolism of warfarin by outcompeting it for similar metabolic pathways (CYP450 enzymes) > increased duration of effect
Elimination
Probenecid decreases the active secretion of B-lactams and cephalosporins in renal tubular cells by competing for transport mechanisms > decreased elimination of B-lactams / cephalosporins
PHARMACODYNAMIC
Homodynamic effects
Drugs bind to the same receptor site (e.g. naloxone reverses the effects of opioids by outcompeting for the opioid receptor sites)
Allosteric modulation
Drugs bind to the same receptor (GABA) but at different sites (e.g. barbiturates and benzodiazepines) > increased effect
Heterodynamic modulation
drugs bind to different receptors but affect the same second messenger system (e.g. glucagon reverses the effects of B-blockers by activating cAMP)
Drugs with opposing physiological actions (but different biological mechanisms)
e.g. GTN vasodilates via guanyl cyclase-cGMP mediated vasodilation, while noradrenaline vasoconstricts via <math display="inline">\alpha</math> agonism
Examiner comments
44% of candidates passed this question
Candidates with a well organised answer scored highly. A list of drug interactions was not sufficient to pass, as the question asked to 'describe' the mechanism of drug interactions. Some candidates described the interaction but did not give examples. Common mistakes included using incorrect examples for a particular mechanism and describing the mechanism of action of drugs instead of drug interactions
The kidneys are involved in hormone production, modification and clearance
Production
Erythropoietin (EPO)
Production:
90% produced in kidneys (~10% in liver) from fibroblast like interstitial cells
Function:
Stimulates the development of proerythroblasts from haematopoietic stem cells in the bone marrow and increases the speed of their maturation
Regulation:
Released in response to hypoxia, low HCT and hypotension.
Decreased in renal failure, increased HCT, inflammation
Renin
Production:
Produced, stored, secreted from JG cells in kidney
Function:
Activation of the renin-angiotensin-aldosterone system leading to increased sodium and water reabsorption, increased vasoconstriction and blood pressure
Regulation:
Stimulated by reduced GFR, direct B1 SNS activation, decreased Na/Cl delivery to JGA
Inhibited by negative feedback
Thrombopoietin
Production
Predominately liver, small amount in kidneys (PCT)
Function
Stimulate megakaryocytes to produce platelets
Regulation
Stimulated by thrombocytopaenia and inflammatory cytokines
Inhibited by negative feedback loop
Urodilatin
A natriuretic peptide secreted by DCT in response to increased Na delivery
Modification
Vitamin D
25-hydroxy vitamin D3 converted into calcitriol in the PCT
Leads to increased Ca absorption from GIT, increased liberation of Ca from bone, increased reabsorption of Ca from DCT in kidney
Stimulated by hypocalcaemia, low vitamin D, high parathyroid hormone levels
Inhibited by low PTH, hypercalcaemia, high calcitriol
Clearance
Gastrin
90% cleared in the kidney in the PCT
Insulin
30% cleared by the kidney in the PCT
Examiner comments
39% of candidates passed this question
It was expected that candidates would discuss the major hormones produced (or activated) by the kidney. These included erythropoeitin, renin and calcitriol. Good answers included the following: the area where the hormone is produced or modified; stimuli for release; factors which inhibit release; and the subsequent actions / effects. Marks were not awarded for hormones that act on the kidney
High scoring answers discussed the three major hormones involved in calcium regulation - parathyroid hormone, vitamin D and calcitonin. For each of these it was expected that candidates include: site of production, stimulus for release, inhibitory factors and actions. In the case of renin it was expected that candidates also include the actions of angiotensin and aldosterone. Very few answers discussed inhibitory factors or negative feedback loops.
Explain the meaning of the components of a Forest plot.
Example answer
Removed from primary syllabus
Examiner comments
65% of candidates passed this question
To score full marks candidates needed to describe each feature of the forest plot provided. This included: odds ratio on the x axis; line of no effect; individual studies on the y axis; point estimate for each study (box position); weighting of the study (box size); pooled effect estimate (diamond position); size of the diamond; and the 95% confidence intervals and their interpretation.
Online resources for this question
Removed from primary syllabus
Similar questions
Removed from primary syllabus
Question 7
Question
Compare and contrast the systemic circulation with the pulmonary circulation
Example answer
Category
Pulmonary circulation
Systemic circulation
Anatomical features
Thin vessel, minimal smooth muscle, elastic
Thick vessel, abundant smooth muscle
Blood volume
~500mls (70kg adult) or 10% total volume
~4.5L (70kg adult) or 90% volume
Blood flow
= cardiac output (~5L/min)
= cardiac output (~5L/min)
Blood pressure
PAP normally ~25/8mmhg (mPAP ~10-15mmHg)
BP normally ~120/80mmHg (MAP ~90mmHg)
Circulatory resistance
PVR ~ 100 dynes.sec.cm-5 ~10% of SVR
SVR approx 1000 dynes.sec.cm-5
Circulatory regulation
Minimal capacity to self regulate (except hypoxic pulmonary vasoconstriction)
Regional blood flow readily regulated at the level of arterioles
Regional distribution of blood flow
Flow affected by gravity, alveolar recruitment, hypoxic vasoconstriction
Significant organ dependant variation in flow (often demand dependant) with minimal affect from gravity. Organs have capacity to autoregulate flow.
Source of nitric oxide and anticoagulants/procoagulants
Filter function
Filters emboli >8um
Filters arterial blood in renal and hepatic vascular beds
Examiner comments
26% of candidates passed this question
This question encompasses a wide area of cardiovascular physiology. As a compare and contrast question this question was well answered by candidates who used a table with relevant headings. Comprehensive answers included: anatomy, blood volume, blood flow, blood pressure, circulatory resistance, circulatory regulation, regional distribution of blood flow, response to hypoxia, gas exchange function, metabolic and synthetic functions, role in acid base homeostasis and filter and reservoir functions. A frequent cause for missing marks was writing about each circulation separately but comparing. For example: many candidates stated 'hypoxic pulmonary vasoconstriction', but did not contrast this to 'hypoxic vasodilation' for the systemic circulation. Frequently functions of the circulations were limited to gas transport / exchange.
Describe the physiological consequences of decreasing the functional residual capacity (FRC) in an adult by 1 litre.
Example answer
Examiner comments
70% of candidates passed this question
High scoring answers began with a definition and normal values, followed by a detailed list of the consequences of decreasing the FRC. Some candidates included descriptions of the normal function of FRC, conditions that decrease FRC and ways of improving reduced FRC. These were not required and did not attract marks. Diagrams require correctly labelled axes, values & units.
Outline how the following tests assess coagulation:
a. Prothombin Time (PT)
b. Activated Partial hromboplastin Time (APTT)
c. Activated Clotting Time (ACT)
d. Thromboelastography (TEG or ROTEM)
Example answer
test
PT
APTT
ACT
TEG/ROTEM
Pathway
Extrinsic + common
Intrinsic + common
Intrinsic + common
Clot formation to lysis
Use
Warfarin monitoring
Screening for coagulopathy
Heparin monitoring
Screening for coagulopathy
Dosing/reversal of heparin in extracorporeal circuits
Guide to product replacement
POC/LAB
Lab
Lab
POC
POC
Sample
Plasma (post centrifuge)
Plasma (post centrifuge)
Whole blood
Whole blood
Principle
Tissue factor added to plasma > activates extrinsic pathway > wait until clot formation
Phospholipid added to plasma (+ activation agent) > stimulates intrinsic pathway > wait until clot formation
Blood added to kaolin clotting activator > stimulates intrinsic pathway > wait until clot formed
Blood distributed into cuvettes. Pin immersed in blood and either cuvette (TEG) or pin (ROTEM) spins. As blood clots > resists movement. TEG: toque exerted on the pin. ROTEM: impedance to rotation detected by optical system.
Normal
11-13 seconds
(INR 0.8-1.2)
30-40 seconds
100-130
INTEM: similar to APTT
EXTEM: similar to PT
CT = time until 2mm amplitude
A10 = amplitude at 10 mins
MCF = time until maximal clot firmness
ML: maximal lysis
Prolonged
Warfarin / vitamin K deficiency / factor II, VII, IX, X deficiency
Different thromboplastins in lab give different PT times > INR standardises
Inadequate mixing of blood
Inadequate blood:citrate ratio
Underfilling shortens ACT
Overfilling, prolongs ACT
Calibration of machine
Examiner comments
61% of candidates passed this question.
Many candidates incorrectly stated that the PT assessed the intrinsic system and that the APTT assessed the extrinsic system. This led to subsequent errors in relating a coagulation test to the appropriate coagulation factors that it assessed. Some candidates produced elaborate diagrams of the coagulation cascade in isolation without relating it to the question.
CVS: Increased BP (mineralocorticoid effect + increased vascular smooth muscle receptor expression to catecholamines)
RESP: decreased airway oedema, increased SM response to catecholamines
RENAL: Na + water retention (mineralocorticoid effect)
Metabolic: Hyperglycaemia, gluconeogenesis, protein catabolism, fat lipolysis and redistribution, adrenal suppression
MSK: Osteoporosis, skin thinning
Immune: immunosuppression + anti-inflammatory effects (decreased phospholipase, interleukins, WBC migration and function)
GIT: Increased risk of peptic ulcers
Pharmacokinetics
Onset
Peak effect 1-2 hours, duration of action 8-12 hours
Absorption
50% oral bioavailability, 100% IV
Distribution
90% protein bound
Small Vd (0.5L/kg)
Metabolism
Hepatic > inactive metabolites
Elimination
Metabolites excreted renally.
Elimination T/12 = ~1 hour
Special points
Risk of reactivation of latent TB / other infections
Examiner comments
54% of candidates passed this question
Hydrocortisone is listed as a Class A drug in the syllabus and as such knowledge of its
pharmacokinetics is expected. No marks were awarded for generic pharmacokinetic statements such as: "average bioavailability", "moderate protein binding", "bioavailability 100% for IV preparation" etc
Right lateral: thyroid gland (lobe), carotid sheath ( common carotid, vagus, IJV)
Left lateral: thyroid gland (lobe), carotid sheath ( common carotid, vagus, IJV)
Neurovascular supply
SNS: sympathetic trunks
PSNS: recurrent laryngeal and vagus nerves
Arterial supply: Branches from inferior thyroid arteries
Venous drainage: Inferior thyroid veins
Surface anatomy of anterior neck (superior --> inferior)
Hyoid bone (C3)
Thyroid cartilage
Cricothyroid membrane
Cricoid cartilage (C6)
Thyroid gland
Sternohyoid muscle just lateral to the midline structures, overlies sternothyroid and thyrohyoid
Layers of dissection in tracheostomy (from anterior --> posterior)
Skin
Subcutaneous tissue
Fat
Pretracheal fascia
Fibroelastic tissue between tracheal cartilage rings
Trachea
Examiner comments
44% of candidates passed this question
Many candidates described how to perform a tracheostomy or the structure of the trachea rather than the relevant anatomical relations. It was expected that answers include anterior, posterior and lateral relations at the correct tracheal level including relevant vascular structures.
Hepatic metabolism (CYP) to noroxycodone, oxymorphone
Elimination
Half-life 2-4hrs, excreted in urine
Reversal
Naloxone (100mcg IV boluses, PRN 3 minutely)
Examiner comments
53% of candidates passed this question
Few candidates covered the pharmacokinetic aspect of the question sufficiently.
No marks were awarded for generic comments such as hepatic metabolism and renal excretion
Outline the anatomy relevant to the insertion of a Dorsalis Pedis arterial cannula (50% of marks). Explain the differences between blood pressure measurement at this site compared to measurement at the aortic arch (50% of marks)
Example answer
Examiner comments
30% of candidates passed this question
The anatomy component of answers frequently lacked required detail. Many candidates listed
the observed differences in the waveforms however an explanation for these differences was
required.
Fatty infiltration > increases risk of arrhythmias
Fibrosis > leads to diastolic dysfunction
Pulmonary artery pressures
Increased
Due to hypoxic pulmonary vasoconstriction (obesity hypoventilation syndrome) and LV diastolic dysfunction from cardiac remodelling
Examiner comments
42% of candidates passed this question
Many candidates did not include enough detail in their answers. Higher scoring answers included more depth such as the following: blood volume, left ventricular changes, arterial blood pressure, pulmonary artery pressures, risks of ischaemia, arrhythmias etc.
List the potential problems resulting from blood transfusion and methods used to minimise them
Example answer
Examiner comments
53% of candidates passed this question
This question required a broad answer. It was generally well answered. Those candidates who scored well had a good structure to their answers e.g. grouping potential electrolyte disturbances together, and infectious risks together etc. and including methods used to minimise these risks in appropriate detail.
- Hepatic hydroxylation by CYP450 system (saturable)
- Wide patient variation (10% population are slow hydroxylators)
Enzymatic hydrolysis ~30% of dose to inactive metabolites
Elimination
Renal elimination of metabolites
T 1/2 = 12 hours
Renal excretion
- unchanged drug (70%) and metabolites (30%) T 1/2 = 6 hours
Monitoring
Phenytoin level 10-20ug/ml
Nil
Examiner comments
35% of candidates passed this question
A table was useful to answer this question. Comparing and contrasting the pharmacology was required to score well rather than listing various aspects of pharmacology. The key properties of the drugs which demonstrate their importance to ICU was required.
Outline the functional anatomy of the kidneys (40% of marks). Outline the regulation of renal blood flow (60% of marks).
Example answer
Examiner comments
67% of candidates passed this question
Candidates who scored well weighted their answers according to the marks allocation outlined in the question and adopted a good structure. A number of candidates confused the roles of tubuloglomerular feedback and the renin angiotensin aldosterone pathway.
Define mixed venous PO2 (20% of marks). Outline the factors that affect this value (80% of marks).
Example answer
Examiner comments
37% of candidates passed this question
This question was in two parts – the first part was worth 20% and candidates were expected to
provide a definition of mixed venous blood as well as the partial pressure of oxygen in mixed
venous blood (including normal range). Good answers also provided the varying PO2 from
different tissue beds that make up mixed venous blood, where the ‘mixing’ occurs (the right
ventricle) and where it is sampled (pulmonary artery).
For the second part of the question, worth 80% of the marks, good answers included the
relationship between mixed venous PO2 and mixed venous O2 content (including the shape and
position of the HbO2 dissociation curve); the variables encompassed in the modified Fick
equation; arterial oxygen content and its determinants; oxygen consumption (VO2); and cardiac
output (CO). Including an outline of how each affects the value of mixed venous PO2.
A number of candidates wrote about mixed venous oxygen saturation. Other common errors
were: missing a number of key factors that affect PO2; and using an incorrect form and/or
content of the modified Fick equation.
Similar PK to argipressin except it is not metabolised, has a longer T1/2
Examiner comments
28% of candidates passed this question
A pharmacology answer template outlining pharmacokinetics and dynamics was required. Candidates failed to score marks for describing the physiology of vasopressin secretion. A number of answers demonstrated limited knowledge about its indications for use and its potential adverse effects.
Explain the potential causes of a difference between the measured end tidal CO2 and the arterial partial pressure of CO2.
Example answer
ETCO2 - PaCO2 gradient
There is normally a gradient between PaCO2 and ETCO2 of 0-5mmHg (where ETCO2 is lower)
The difference between the values is due to alveolar dead space
Alveolar dead space is due to alveoli which are ventilated but not perfused (e.g. west zone 1 lungs)
These alveoli do not participate in gas exchange (there is no perfusion), thus contain very little CO2 and a lot of O2 (the same amount as in inspired air)
This relatively CO2 deplete gas mixes with the rest of the expired gas, diluting the ETCO2 reading, thus leading to an observed discrepancy
Note: It is not due to anatomical dead space as this gas has already been washed out in the early stages of exhalation and thus does not contributed to ETCO2
Healthy/awake patients have near zero alveolar dead space, so near zero gradient
Factors affecting ETCO2 - PaCO2 gradient
Changes in pulmonary perfusion
Global reduction in pulmonary perfusion
e.g. pHTN, heart failure, Cardiac arrest, Severe shock
Regional decreases in pulmonary perfusion
e.g. pulmonary embolism, fat embolism
Changes in ventilation
Excessively high PEEP --> increased West Zone 1
Measurement error
Inline HME filters
Timing of measurement (measuring before end-expiration)
Poor / loss of ETCO2 calibration
Interference from other gases (e.g. N2O and collision broadening)
Physiological factors
Increasing age > increased gradient
Examiner comments
30% of candidates passed this question.
Many candidates didn’t distinguish between the different types of dead space. In general this topic was not well understood.
Most candidates attempted a structure however did not expand the answers within the categories: e.g. a passing mention of glucose homeostasis is insufficient to score full marks for the carbohydrate metabolism category.
Draw and label a left ventricular pressure volume loop in a normal adult (40% of marks). List the information that can be obtained from this loop (60% of marks).
End diastolic pressure-volume relationship (EDPVR)
Describes elastance, Non linear
End systolic pressure-volume relationship (ESPVR)
Describes contractility, Linear
Arterial elastance
Approximation of afterload
Line between EDV and ESP
Areas
Total mechanical work (combination of stroke and potential work)
Stroke work (inside PV loop)
Stored potential work (outside loop, under ESPVR line)
Examiner comments
65% of candidates passed this question.
Many candidates lost marks for poor quality diagrams with inaccurate labelling. An accurate diagram was required. Many answers lacked sufficient detail regarding contractility and afterload.
Describe the characteristics of a drug that influence its excretion by the kidneys
Example answer
Renal excretion of drugs is related to factors which affect
Filtration at the glomerulus
Secretion into the tubules
Reabsorption in the tubules
Factors affecting glomerular filtration
GFR
Increased GFR (e.g. increased CO) will lead to increased filtration and clearance of hydrophilic drugs
Drug size
Increasing drug size = decreased renal clearance
Only drugs <7kDa (weight) or <30 Angstrom units (width) are able to pass the capillary BM
Protein binding
Only unbound drugs can pass the glomerular BM (hence highly protein bound drugs are poorly filtered)
Charge
Negatively charged molecules cannot readily pass BM (as it is also negatively charged)
Factors affecting drug secretion
Active process
Protein binding, renal blood flow (GFR) as per above
Concentration: Increased concentration = increased secretion (until transporters are saturated)
Concomitant drugs - competition for receptors
Factors affecting drug reabsorption
Can be active or passive (most are passive)
Also depends on charge (ionised drugs cannot pass through BM) and become trapped in the urine
Ionisation depends on pH urine, pKa drug (acidic drugs are ionised in alkaline urine)
Concentration (as passive diffusion depends on concentration gradient)
Urine flow rate
Increased urine flow rate > reduces concentration of drug in urine > increased concentration gradient + elimination
Examiner comments
29% of candidates passed this question.
Drug characteristics that might influence the renal excretion processes include charge, size, solubility, and binding to specific structures or protein. Whether the drug is unchanged versus metabolised can influence these factors. This question tests core knowledge of pharmacology principles and should be answered with equations, graphs or simple clear descriptions of physical and chemical principles. Extended examples and hedged statements about “influencing†without the direction, magnitude and necessary conditions for the influence did not score marks.
Question 13
Question
Describe the cardiovascular effects of a sudden increase in afterload.
Example answer
Afterload
Force that must be overcome prior to the sarcomere being able to shorten during contraction (i.e. the forces opposing ventricular ejection)
CVS effects
HR
If the increase in afterload is associated with increase in carotid pressure > baroreceptor reflex activation > compensatory decrease in HR
SV
The increased afterload > earlier closure of the AV valve (increased diastolic pressure) and decrease in velocity of myocyte shortening > increased end-systolic volume (and pressure) > decreased stroke volume > decreased CO
Preload
Increase in afterload > decrease in SV > increase in LV end systolic volume (and pressure) > Increase in EDV (preload)
Contractility
Increases due to the Anrep effect
Increase in afterload > increased LV EDP > frank starling effect > Calcium accumulation > increased contractility > increased SV
Cardiac output
Decreases in short term
Ideally recovers quickly if the compensatory mechanisms work
If the LV is impaired, or the body is unable to compensate > LV heart failure
Myocardial oxygen consumption
Increases due to increased contractility and increased work to overcome afterload
It was expected the answer would start with a definition of afterload and then proceeded to indicate what effects this increase in afterload would have on ventricular end-systolic pressure, ventricular end-diastolic pressure, left atrial pressure, cardiac output, myocardial oxygen demand and myocardial work, coronary blood flow and systemic blood pressure.
Most candidates who failed to pass this question submitted answers that were just too brief, only including a small subset of the material required. Very few candidates included any mention of myocardial oxygen demand or myocardial work or the impact upon the cardiac output. A number of candidates included a detailed description of the Sympathetic Nervous System and the Renin-Angiotensin system, material which was not asked for. There were quite a number of incorrect perceptions about what effect a sudden increase in afterload would have on the systemic blood pressure. Candidates who mentioned the baroreceptor response and the stretch receptor response where rewarded with additional credit.
Outline the role of the liver in drug pharmacokinetics
Example answer
Absorption
The liver will affect the bioavailability of drugs which are subject to first pass metabolism
Hence, oral absorption, high PR, > subject to hepatic extraction and metabolism
Drugs which are not subject to first pass metabolism e.g. inhalation, intravenous, IM ,> higher bioavailability if hepatically metabolism/cleared
Liver dysfunction > alter first pass metabolism
Distribution
The liver is responsible for producing majority of the proteins that drugs bind
Hence, for highly protein bound drugs (e.g. warfarin), small changes in protein levels, can lead to large changes in the proportion of unbound (active drug)
Liver dysfunction > alter protein binding
Metabolism
The liver is a primary organ of drug metabolism and biotransformation
E.g. liver damage > unable to process paracetamol > increased toxicity
Elimination
The hepatic system is important for drug elimination
Drugs with a high hepatic extraction ratio, will also be dependant on the hepatic blood flow. Drugs with a low hepatic extraction ratio will depend on the function of the liver
For hydrophilic drugs, that are highly protein bound, decreased proteins related to hepatic dysfunction will increase elimination
Biliary section
Drugs which rely on biliary exertion will be retained in liver dysfunction
Portal hypertension > shunting of blood > decreased first pass metabolism
Examiner comments
62% of candidates passed this question.
Most candidates structured their answer to this question well – they were aware of first pass metabolism and the effect of protein synthesis upon volume of distribution of drugs. Knowledge concerning Phase I and Phase II reactions was frequently inadequate. Many candidates were aware that these processes as well as inactivating or activating drugs resulted in increased water solubility to aid excretion via bile or urine. Few candidates discussed the significance of the large blood flow to the liver or the implications of high and low extraction ratios especially in relation to liver blood flow
Question 24
Question
Describe the ideal sedative agent for an Intensive Care patient (50%). How does midazolam compare to this (50%)?
Example Answer
Name
Midazolam
Ideal sedative agent
Class
Benzodiazepine (sedative)
-
Pharmaceutics
Clear colourless solution
pH 3.5.
Diluted in water.
- Water soluble
- Chemically stable with long shelf life (various temperatures)
- Does not need reconstitution.
- Compatible w. all drugs / IVF
- Enantiopure preparation
- No additives
Routes of administration
IV, IM, S/C, intranasal, buccal, PO
Multiple routes of administration available
pKa
6.5
-
Dose
Variable
Predictable response for a given weight based dosing regime
Pharmacodynamics
MOA
Midazolam (BZD) binds to GABAA receptors (ionotropic ligand gated channel) in the CNS. Cl enters > hyperpolarisation.
No side effects, including no cardiorespiratory depression or emergence delirium
Pharmacokinetics
Onset
peak effect 2-3 minutes (IV), offset variable
Rapid onset / offset
Absorption
~40% oral bioavailability
- Absorbed well, but sig. 1st pass metabolism
Absorbed well from all routes, including oral and inhaled with minimal first pass metabolism
Distribution
Vd = 1L / kg
95% protein bound
Vd = <0.3L/Kg
Minimal protein binding (decreases availability)
Metabolism
Hepatic metabolism by hydroxylation
Active (1-a hydroxymidazolam) and inactive metabolites
Either no metabolism or organ independent metabolism with inactive metabolites (prevents accumulation)
Elimination
Renal excretion
T 1/2 = 4 hours
Rapidly cleared with a short and predictable half life and small CSHT
Reversal
Flumazenil - antagonist (reversal agent)
Readily reversible with no rebound/side effects
Examiner comments
60% of candidates passed this question.
Candidates who had a structured approach (i.e. pharmaceutical, pharmacokinetic, pharmacodynamic) provided more content and scored higher. Candidates who also approached pharmacodynamic effects in an organ system based approach scored higher. Relating a pharmacokinetic property of midazolam (e.g. volume of distribution or half-life) to a un/desirable attribute e.g. offset of action and accumulation displayed a greater understanding of the question. For many candidates, the description of an ideal drug contained more detail and candidates were not able to adequately state how midazolam compares.
Systemic corticosteroids should be given to all mod-severe asthma > improve outcomes
MOA: bind to cytoplasmic glucocorticoid receptors > change in gene transcription > down-regulates the synthesis of proinflammatory cytokines/mediators
Effects: increased B receptor responsiveness, decreased inflammation, decreased mucus secretion
Side effects: numerous! Depends on dose/duration. Examples:
Short term: hyperglycaemia, hypokalaemia, immunosuppression, insomnia/confusion/psychosis,
Long term: cushings, osteoporosis, skin thinning, weight gain, immunosuppression
Other potential treatment options (and MOA)
Magnesium sulphate > inhibits L type calcium channels > bronchodilation/SM relaxation
Ketamine >inhibits L type calcium channels > Bronchial smooth muscle relaxation
Aminophylline > PDEI > SM relaxation / bronchodilation
Heliox > Improves laminar airflow > may improve ventilation
Inhaled anaesthetics (e.g. sevoflurane)
Montelukast (leukotriene receptor antagonist used in children)
Examiner comments
71% of candidates passed this question.
Asthma drugs are typically categorised according to mechanism of action. A reasonable alternative is to categorise by clinical use, e.g. short acting, long acting, preventer, rescue etc.
A lot of emphasis in marking was placed on an understanding of the beta-adrenergic pathway, its secondary messenger system and how this medicates smooth muscle relaxation. Candidates whose answers had structure as well those who described the wide range of drugs used to treat asthma scored well.
Question 9
Question
Describe the immunology and drug treatment of anaphylaxis.
Answer
Anaphylaxis
Life threatening systemic hypersensitivity reaction
May be immune mediated (IgE or non IgE) or non immune mediated
IgE immune mediated anaphylaxis (a Type-1 hypersensitivity reaction)
Initial contact between a B-cell and an antigen (allergen) leads to the formation of a IgE against it
The specific IgE then binds to Fc receptors on mast cells (in tissues) and basophilis (in circulation)
Further exposure of the antigen leads to formation of cross links between IgE-Fc complex and the antigen which leads to activation and release of pre-synthesised mediators
May prevent biphasic responses / prolonged course of illness
Antihistamines
e.g. loratadine, premethazine
Symptomatic treatment strategy in mild disease
May provide some relief from pruritis/rash (via blocking H1 receptor)
Minimal effects on systemic mast cell and basophil degranulation
No effects on outcomes
Not recommended for severe disease
Glucagon
For patients who have taken b-blockers (and thus have reduced responsiveness to adrenaline)
Examiner comments
32% of candidates passed this question.
It was expected candidates would detail the process of IgE mediated type I hypersensitivity reaction with some discussion of the mediators (Histamine / tryptase and others) and their consequences. Some detail describing time frame of response and the pre-exposure to Antigen (or a similar Antigen) was expected. Drug treatments would include oxygen and fluids as well as more specific agents such as adrenaline and steroids. Adrenaline is the mainstay of therapy and some comment on its haemodynamic role and prevention of ongoing mast cell degranulation was required.
Better answers noted steroids take time to work and some also discussed the role of histamine blocking agents
Outline the influence of pregnancy on pharmacokinetics
Example answer
Absorption
Oral
Nausea and vomiting in early preg > reduced PO absorption
Increased intestinal blood flow (due to increased CO) > increased PO absorption
Decreased gastric acid production > increased pH > unionised drugs absorbed more
Delayed gastric emptying peri-labour may increase/decrease absorption depending on drug
IM / SC / Transdermal
Increased absorption due to increased CO + increased skin/muscle blood flow
IV
Faster IV onset due to increased CO
Neuraxial
Decreased peridural space (venous engorgement) > decreased dose required
Distribution
Volume of distribution
Increased total body water > increased Vd for hydrophilic drugs
Increased body fat > increased Vd for lipophilic drugs
Plasma proteins
Decreased protein binding (increased free fraction) due to reduced concentrations albumin and a-1 glycoprotein
Metabolism
Hepatic
Some metabolic enzymes reduced / some increased (due to progesterone/oestrogen ratio)
Leads to variable drug responses
E.g. increased metabolism of midazolam, phenytoin, but decreased caffeine.
Placenta metabolises some drugs (COMT and MOA enzymes > metabolises catecholamines)
Decreased plasma cholinesterase (though no change in Succinylcholine effect)
Elimination
Renal
Increased clearance due to increased GFR (e.g. gentamycin)
Hepatobiliary
Decreased clearance due to cholestatic effects of oestrogen (e.g. rifampicin)
Resp
Increased volatile washout due to increased minute ventilation
Examiner comments
47 % of candidates passed this question.
Most candidates divided the answer into effects on absorption, distribution, metabolism and elimination, which is a good way of presenting the answer. However, the good candidates also mentioned effects on the foetus due to ion trapping caused by the more acidic foetal blood.
Many candidates forgot to include effect on epidural administration of drugs in pregnancy caused by engorged epidural veins during labour.
Candidates lost marks for omitting the effect of increased cardiac output on the rate of distribution of IV drugs to effector sites, the effect of increased hepatic blood flow on drugs with high intrinsic clearance, the increased clearance of drugs with renal clearance due to increased GFR & renal plasma flow
Question 23
Question
Compare and contrast the mechanism of action, spectrum of activity and adverse effects of benzyl penicillin and fluconazole.
Answer
Benzylpenicillin
Fluconazole
Mechanism of action
Penicillin antibiotic
Both disrupt cell wall synthesis (but different mechanisms): Binds to penicillin binding proteins > inhibits peptidoglycan cross linking > bactericidal
Azole antifungal
Inhibits the fungal CYP450 enzyme responsible for ergosterol production (needed for fungal cell membrane synthesis) > cell death
Spectrum of activity
Narrow spectrum penicillin
Covers: Most GPC (staph, strep, enterococci), some GPB (e.g. listeria), very few GNC (e.g. Neisseria sp). Does not cover: MRSA, CRE, VRE, manty other GN bacteria + anaerobes, all fungi/yeasts, all parasites/ protozoans
Narrow spectrum azole
Covers: Candida and cryptococcal species Does not cover: some candida sp (e.g. krusei), aspergillus and most other fungi/yeast, all bacteria (GP and GN), all parasites/protozoa
Adverse effects
CNS: confusion, coma, seizure
CVS: Nil major
RESP: Nil
GIT: Raised LFTs, nausea and vomiting and abdominal pain, pseudomembranous colitis
HAEM: agranulocytosis
RENAL: Interstitial nephritis
IMMUNO: rash, allergy, anaphylaxis
OTHER: less drug interactions, not a teratogen
To pass this question each of the three components needed to be compared and contrasted for both agents. A tabulated answer helped in this regard but was not essential.
Some answers included information that could not gain marks, as it was not directly relevant to the question asked (e.g. presentation and dose).
In spectrum of activity, as well as what important organisms the agents were effective against, marks were also given for the important organisms that they were not effective against (e.g. MRSA and beta-lactamase producing organisms for penicillin G; and aspergillus for fluconazole).
In general, of the two agents, fluconazole was the least well answered. For example, a common omission either in mechanism of action or in adverse effects was that fluconazole inhibits microsomal P450 enzymes.
Some candidates confused fluoroquinalone with fluconazole.
CNS: increased osmolality of ECF > osmotic fluid shifts out of cells > decreased ICP/IOP
CVS: initial rise in MSFP>preload>BP (fluid load) which then decreases with diuresis > hypotension
RESP: Pulmonary oedema (increased in ECF volume)
Renal: Increases Na, Cl, NAGMA, osmolality
MSK: necrosis/phlebitis if given peripherally/extravasates
CVS: increased ECF > overload
RESP: pulmonary oedema (fluid overload)
Unstable at low temps, leads to diuresis, more cumbersome to monitor
Needs central access, can cause hypernatraemia,
Examiner comments
8 % of candidates passed this question.
A structured approach is important and a table worked best for most candidates, although a few attempted this in free text. Despite attempting a structured answer very few candidates provided information in regards to preparation, dose, monitoring of osmolarity, adverse effects or contraindications. Understanding of the action of these drugs was expected and factual inaccuracies were common with many candidates suggesting hypertonic saline acts as an osmotic diuretic. Better answers mentioned other potential mechanisms of action of mannitol. Many candidates failed to appreciate the impact on raised intracranial pressure.
Compare and contrast the pharmacology of valproic acid and carbamazepine
Example Answer
Name
Sodium valproate (valproic acid)
Carbamazepine
Class
Anticonvulsant
Anticonvulsant
Indications
- Migraine
- Epilepsy (simple-complex and focal-generalised)
- Status epilepticus
- Epilepsy
- Trigeminal neuralgia
- Bipolar disorder
Pharmaceutics
Enteric coated tablets, oral liquid
Powder for reconstitution
IR and MR tablets
Oral liquid
Routes of administration
IV, PO
PO
Dose
15-30mg/kg in divided doses
400mg-1.2g in 2/3 divided doses
Pharmacodynamics
MOA
Stabilises Na channels in their inactive state, thereby inhibiting the generation of further action potentials. Also by stimulating GABAergic inhibitory pathways
Stabilises Na channels in their inactive state, thereby inhibiting the generation of further action potentials. Also by stimulating GABAergic inhibitory pathways
Monitor LFTs first 6 months given risk of liver failure
Examiner comments
6% of candidates passed this question.
Both these agents are listed as “level B†in the syllabus pharmacopeia and as such a general understanding of each class and relevant pharmacokinetics and pharmacodynamics was expected. Most candidates had better knowledge of valproate than carbamazepine. Some description of the toxicological features for intensive care practitioners was expected.
- Blocks K channels (Class III effects) prolonging repolarisation and therefore refractory period.
- Decreases velocity of Phase 0 by Blocking Na channels (Class I effects)
- Non-competitive inhibition of Ca channels prolonging depolarisation + AV nodal conduction time (Class IV effects)
- Slows AV/SA nodal conduction via anti-adrenergic activity (Class II effects)
Effects
Rhythm / rate control of tachyarrhythmias
Side effects
Side effects worsen/increase with duration of therapy!
0.21 - 1.0 FiO2 (generally targeting SaO2 >94%; or 88-92% on CO2 retainers; though exact target not entirely evidenced based)
Pharmacodynamics
MOA
Oxygen is delivered to tissues for aerobic metabolism via oxidative phosphorylation
Effects
RESP: improved oxygen saturations (may also improve DO2), decreased respiratory drive (very minimal), pulmonary toxicity (free radical generation), may worsen V/Q mismatch (impairs HPVC), drying of mucous membranes
CVS: decreased pulmonary vascular resistance (vasodilation) due to reversal of HPV, increased HR/SV/SVR if hypoxic (via chemoreceptor reflex) > increased CO and BP CNS: anxiety, nausea, visual changes (neonates), seizures (hyperbaric hyperoxia), decreased CBF (vasoconstriction) MET: oxidative phosphorylation > ATP production
Pharmacokinetics
Absorption
Diffusion across the alveolar capillary membrane.
Rate of diffusion is governed by Fick's Law and is therefore proportional to the lung area, gas diffusion constant, partial pressure gradient and inversely proportional to membrane thickness
Distribution
Bound to plasma Hb (98%)
Dissolved in plasma (<2%) - related to Henrys Law
Metabolism
Metabolised in mitochondria during the Citric acid cycle, to produce ATP and generate CO2 and H2O
Elimination
Exhalation of CO2 via lungs
Special points
Examiner comments
35% of candidates passed this question.
Use of a general "pharmacology" structure to answer this question would help avoid significant omissions such as only discussing pharmacokinetics or only discussing pharmacodynamics. Oxygen has a well described list of pharmacodynamics effects that includes, cardiovascular, respiratory and central nervous system effects. Candidates’ knowledge of the pharmaceutics was limited for a routine drug. It was expected candidates would mention the potential for oxygen toxicity including a possible impact on respiratory drive in selected individuals, retrolental fibroplasia and seizures under some circumstances. Many candidates did not answer the question asked, and instead focussed on the physiology of oxygen delivery and binding of oxygen to haemoglobin
Describe the pharmacological effects of paracetamol (40% marks). Outline its toxic effects and their management (60% marks).
Example Answer
Pharmacological effects
MOA
Not entirely understood
Analgesic effect thought to be related to
Decreased central prostaglandin synthesis by inhibition of COX-3
Modulation of 5-HT pathways (increased descending inhibition)
Activation of endocannabinoid (CB1) and capsaicin (TRPV1) receptors
Antipyretic effect thought to be due to decreased PG synthesis in hypothalamus by COX-3
Effects/side effects
CNS: analgesia, antipyretic
CVS: Hypotension (IV preparation, related to excipients)
GIT: deranged LFTs, liver failure/damage in high doses/toxicity (below)
Other: hypersensitivity reactions
Toxic effects
Mechanism
Paracetamol is normally hepatically metabolised
Principally it is conjugated (glucuronide and sulfate) > eliminated
Small amounts undergo oxidation > toxic metabolites (NAPQI)
In regular amounts, the NAPQI can be neutralised by hepatic glutathione (anti-oxidant)
In excess/toxicity, the conjugative pathways are saturated and there is increased oxidation > increased NAPQI. The hepatic glutathione is exhausted > build up of NAPQI > liver damage
Increased inactivation of the toxic metabolites (NAPQI) > reduced liver damage
200mg/kg over first 4 hours, then 100mg/kg over next 16 hours
Supportive care
Fluids, antiemetics, etc
Complications of acute liver failure
Dialysis, ventilation etc
Examiner comments
63% of candidates passed this question.
This question was generally well answered with narrow variance; very few candidates discussed factors predisposing to hepato-toxicity or renal toxicity. Discussion of pharmacokinetics only gained marks when relevant to toxicity.
CVS: hypotension, bradycardia, AV Block, arrhythmia
CC:CNS ratio = 7 (lower number = more cardiotoxic)
Other: allergy, anaphylaxis, methaemaglobinemia,
Pharmacokinetics
Onset
Rapid onset (1-5 minutes)
Absorption
IV > Epidural > subcut .
Oral bioavailability ~35%.
S/C Dependant on site of injection, blood flow, use of adrenaline.
Distribution
70% protein bound
Vd ~0.9L/kg.
Crosses BBB
Metabolism
Hepatic (CYP450 dealkylation)
Some active metabolites
Elimination
Renal excretion (98%) of metabolites
Half life ~90mins --> Increased with adrenaline (SC).
Reduced in cardiac/hepatic failure.
Special points
Intralipid can be used in LA toxicity
Examiner comments
71% of candidates passed this question.
The first part of this question was answered well by most candidates.
Generally, the second part of the question was poorly organised by many candidates, the consequence being that many opportunities for picking up marks were lost. A brief statement as to what lignocaine is, its presentations and dose, some facts about PD and PK followed by a few lines on toxicity (CC/CNS ratio) was mostly what was required. Only a few candidates mentioned lignocaine toxicity.
Describe the factors affecting drug absorption from the gastrointestinal tract
Example answer
Drug factors
Concentration of drug
Increased concentration gradient = more rapid absorption
Physical form of drug
Liquid drug > faster gastric transit time
Ability to dissolve (e.g. enteric coatings) > delays time
MR preparations > delayed absorption
pKa of drug
Weaker acids better absorbed
Lipophilicity of the drug
Lipophilic drugs better absorbed
Size of the drug
Smaller = faster/more readily absorbed
Drug-drug interactions
E.g. vitamin c increases absorption of iron
activated charcoal prevents absorption of some drugs through chelation
Patient factors
Gastric emptying time
Diarrhoea, constipation, ileus will all influence this > slow/fasten absorption
Food intake
Drugs can interact with food (e.g. iron absorbed better with orange juice due to vitamin C)
Altered surface area of the GIT
E.g. chrons or surgical short gut > decreased absorption
GIT blood flow
Reduced blood flow > decreased rate of absorption
Biliary function
Emulsifying effect of bile important for absorption of fat soluble vitamins and steroids
Pancreatic function
Examiner comments
45% of candidates passed this question.
This is a very broad and open question. While a structured approach was useful, a sound knowledge of first principles or even being able to “think on the fly†would have provided candidates with enough opportunities to generate a pass.
2013 (1st sitting)
Question 1
Question
List the different mechanisms of drug actions with examples
Answer
Classification
Mechanism
Example
NON RECEPTOR
Physiochemical actions
Drug exerts its effects due to its physiochemical composition
Antacids (basic) which neutralise gastric acid > decreased GORD symptoms
Colligative properties
Drug exerts its effect due to the concentration of solute, not the identity of the solute
Mannitol > increased plasma osmolality > diuresis
Actions on enzyme systems
Decreased concentration of the substrate or product of the enzyme system
ACE inhibitors > decreased concentration of angiotensin II
Prodrugs
Converted from inactive drug > active drug following administration
Levodopa > dopamine
Alteration of a carrier protein
Alter the normal function of a carrier protein
Frusemide which inhibits NaK2Cl co transporter in LOH > diuresis
Voltage gated ion channels
Activated by changes in membrane potential near the ion channel
Local anaesthetics > block voltage gated Na channels
RECEPTOR
Binding to intracellular receptors
Lead to changes in cell function by altering DNA/RNA transcription
Steroids (nuclear receptor)
Binding to ionotropic receptors
Lead to changes in cell function by allowing flow of ions down a concentration/electrical gradient
A good answer to this question required candidates to think broadly about how drugs act and have a system for classifying their actions. One possible classification is action via receptors or non-receptor actions. Many candidates used categories such as physiochemical, receptor and enzymes. Common problems were failure to mention a whole class of drug actions e.g. drugs acting via voltage-gated ion channels or gene transcription regulation. Candidates also gave far too much detail in some sections e.g. a description of zero order and first order kinetics is not required. Candidates often did not give examples of the drug action they described.
Tranexamic acid is a drug used to reduce bleeding in trauma or surgery. It is also used for hereditary angioedema and menstrual bleeding. It is being increasingly used in critically ill patients. As a Level B listed drug within the Primary Syllabus candidates would be expected to know it in some depth. Often basic information such as mechanism of action, pharmacokinetics and adverse effects was lacking.
Most candidates answered the question under the subheadings absorption, distribution, metabolism and elimination. However, they didn’t give any details of the direction or mechanism of change, often used vague statements without specifically addressing the question and failed to give examples. The impact of the shock state on different kinetic parameters including absorption from skin, tissue, muscles, enteral absorption and inhalational was often overlooked. Similarly, the consequences of changes in volume of distribution, protein binding (e.g. albumin and globulin, ionisation) was poorly understood as was alteration in liver and kidney function. Although this topic is very broad candidates were asked to only outline the details of this topic
Question 23
Question
How do chemical messengers in the extracellular fluid bring about changes in cell function? Give an example of a chemical messenger for each mechanism noted
Example Answer
Chemical messengers (ligands) bind to receptors to elicit a response.
Receptors may be located on the cell surface or within the cell.
Intracellular receptors
Proteins located in the cytosol or cell nucleus
Activated by lipid soluble ligands (as they must be able to penetrate the lipid bilayer)
Lead to changes in cell function by altering DNA/RNA transcription
Example:
Steroids (nuclear receptor) and milrinone (cytosolic receptor)
Specific effects depend on the ligand and the receptor location
Ionotropic receptors
Membrane spanning proteins
Lead to changes in cell function by allowing flow of ions down a concentration/electrical gradient
Examples:
GABAA receptor: GABA binds > Cl channel opens > hyperpolarisation > inhibitory post synaptic potential (drug example = benzos)
nAChR receptor: acetylcholine binds > non selective cation channel opening - Na/K/Ca > depolarisation > excitatory post synaptic potential (drug example is sux, which is agonist)
NMDA receptor: glutamate binds > non selective cations > Na/K/Ca > depolarisation > excitatory post synaptic potential (drug example = ketamine which is an antagonist)
Metabotropic (G protein coupled) receptors
Transmembrane proteins with 7 regions
Lead to changes in cell function through chemical second messenger systems
Activation of the extracellular domain > conformation change in intracellular domain > activation of G proteins > second messenger pathway
Overall answers lacked structure and depth, to what is a very fundamental topic. This topic is generally covered within the opening chapters of most physiology texts. Common errors were not answering the question, writing lists rather than describing and explaining, and poor categorisation. Candidates were expected to mention and give example for mechanisms such as hormones binding to cytoplasmic or intra-nuclear receptors, binding to transmembrane receptors coupled to G proteins, cAMP, cGMP, tyrosine kinase, etc.
Mother: gastritis, nausea, vomiting, platelet dysfunction, AKI
Baby: premature closure of ductus arteriosus
Examiner comments
Candidates often appeared to have a sufficient awareness of the choice of drugs (e.g. oxytocin analogues, ergot alkaloids, beta-receptor agonists, calcium channel blockers, etc.), but then failed to produce sufficient depth of knowledge to adequately describe their mechanisms of action in respect to uterine tone. Candidates are reminded that if asked to mention side effects, mentioning side effects of greatest relevance to intensive care (e.g. bronchospasm) in addition to the more generic side effects (e.g. rash).
Describe the pharmacology of short acting insulin (actrapid).
Answer
Name
Short acting insulin (e.g. actrapid)
Class
synthetic polypeptide hormone
Indications
Diabetes / hyperglycaemia
Hyperkalaemia (in conjunction with dextrose)
B-blocker toxicity (high dose insulin therapy)
Pharmaceutics
Clear colourless solutions (generally 100IU/ml)
Routes of administration
SC, IV
Dose
Variable, titrated to effect (generally bSL)
Pharmacodynamics
MOA
The same pharmacodynamic profile of endogenous insulin
> Insulin binds to the alpha subunit of the insulin receptor (tyrosine kinase receptor). Leads to activation of tyrosine kinases on intracellular domain > phosphorylates IRS > cellular cascade
Effects
Increased: glucose uptake in cells, glycogenesis, protein synthesis
Decreased: BSL, gluconeogenesis, lipolysis, proteolysis
Cellular shift of potassium (intracellular) due to increased Na/K activity
Side effects
Hypoglycaemia (excessive dosing) --> decreased LOC, seizures, death
BSL levels (frequency depends on indication, glycaemic stability, route etc)
Examiner comments
In general candidates lacked a sufficient depth of knowledge for this commonly used drug. Some candidates confused actrapid with novo rapid. A structured approach (e.g. pharmaceutics, mode of action, pharmacokinetics, etc.) was expected.
Portal hypertension > shunting of blood > decreased first pass metabolism > accumulation
Elimination
Liver failure > decreased hepatic blood flow > decreased elimination of drugs with high hepatic extraction ratio
Liver failure > decreased elimination of drugs with low hepatic extraction ratio (regardless of HBF)
Liver failure > decreased plasma proteins > increased unbound fraction drug > increased renal elimination of hydrophilic drugs
Liver failure > decreased elimination on lipophilic drugs excreted in biliary system
Examiner comments
59% of candidates passed this question.
Good answers were structured using pharmacokinetic and pharmacodynamics headings.
They included some mention of changes in absorption, volume of distribution (an increase
in Vd in liver failure), altered protein binding, altered metabolism and thus change in
clearance, and changes in excretion (decreased biliary excretion of drugs). In respect to
pharmacodynamics candidates could have mentioned increased sensitivity and prolonged
action of sedative drugs, oral anticoagulants, etc. Good candidates also differentiated for
acute (often hepatocellular dysfunction) and chronic liver failure (cirrhosis and changes in
liver blood flow). Common problems were not using a logical structure to answer the
question and stating an effect but not describing how this affected pharmacology. For
example stating decreased albumin production but then not stating the consequence of this
on drug distribution. Primary examination questions may often require candidates to
integrate knowledge from across different sections of the syllabusor apply basic
physiological or pharmacological principles.
Question 9
Question
Classify the anti-arrhythmic drugs using the Vaughan-Williams classification (30% of marks). Compare and contrast the electrophysiological effects of Class 1 anti-arrhythmics (70% marks).
Answer
Class
Ia
Ib
Ic
II
III
IV
Mechanism
Blocks Na channels
Blocks Na channels
Blocks Na channels
\beta-adrenergic blockade
Blocks K+ channels
Blocks Ca channels
Example
Procainamide
Lidocaine
Flecainide
Propranolol Esmolol, Atenolol Sotalol
Amiodarone (also I,II,IV effects) Sotalol
Verapamil Diltiazem
Effects on
Phase 0
↓
-
↓
-
-
-
Conduction velocity
↓
-
↓
↓
↓
-
ERP
↑
↓
↑
↓
↑
-
APD
↑
↓
-
↑
↑
↓
QRS duration
↑
-
↑
-
↑
-
QTc
↑
↓
↑
↓
↑
-
Drugs not included
Digoxin
Adenosine
Magnesium
Examiner comments
Most candidates displayed a basic knowledge of the Vaughan-Williams classification and gave an example of each class. The remainder of the question lent itself very well to a tabular format. Better answers included the effect on the action potential (diagrams were useful here), channel dissociation kinetics (this was frequently omitted) and examples from each class of drug. There is an excellent table in Stoelting which answers this question nicely. Marks were not awarded for clinical effects. Overall, this question was generally well answered.
Question 13
Question
Describe the effects of obesity on drug pharmacology (70% of marks). Give examples of those drugs that illustrate those effects (30% of marks)
Example answer
Obesity
BMI > 30
Alters all aspects of pharmacology to varying degrees
PHARMACOKINETICS
Absorption
Increased gastric emptying > increased absorption
Decreased subcutaneous blood flow (increased adiposity, no increase in vascularity) > slow rate of SC absorption
Difficulty with IM administration due to tissue (may lead to inadvertent SC injection)
Increased CO > delayed onset of inhalation anaesthetics
Distribution
Increased body adiposity > Increased volume of distribution of lipid soluble drugs (e.g. benzodiazipines, thiopentone)
Small (relative to body fat) increased Vd for hydrophilic drugs e.g. gentamicin (due to increased blood volume, total body water).
Generally lipid soluble drugs dosed on actual body weight, hydrophilic drugs on ideal body weight
Metabolism
Increased hepatic blood flow (due to increased CO) = increased clearance of high extraction ratio drugs (flow dependant extraction) e.g. propofol
Decreased hepatic blood flow (due to dysfunction, fatty infiltration) > decreased hepatic extraction and metabolism
Increased activity of plasma and tissue esterases > increased metabolism/clearance of drugs using these systems (e.g. remifentanil)
Increased pseudocholinesterase levels in obesity (sux to be doses on total body weight)
Elimination
Increased GFR (due to increased CO) – increased renal clearance of hydrophilic drugs (e.g vancomycin)
Decreased GFR due to diabetic nephropathy = decrease renal clearance
Due to distribution, lipid soluble drugs may have increased elimination half life
PHARMACODYNAMICS
Receptor resistance (e.g. insulin resistance in obesity)
Examiner comments
36 % of candidates passed this question.
This question could be approached by describing the effects of obesity on drug distribution,
binding and elimination. Candidates that took this approach generally did better than those
with a less structured approach. With obesity, fat body mass increases relative to the
increase in lean body mass leading to an increased volume of distribution particularly for
highly lipid soluble drugs, e.g. midazolam. However, the dosing of non-lipid soluble drugs,
e.g. non-depolarising muscle relaxants, should be based on ideal body weight. An increase in
blood volume and cardiac output associated with obesity may require an increased loading
dose to achieve a therapeutic effect, e.g. thiopentone. Plasma protein binding of drugs may
be decreased due to an increased binding of lipids to plasma proteins, resulting in an
increased free fraction of drug. A reduction in plasma protein concentration due to an
increase in acute phase proteins may also result in decreased plasma protein drug binding
and increased free fraction of drug. Pseudocholinesterase levels are increased in obesity and
therefore the dose of suxamethonium should be based on total body weight. Plasma and
tissue esterase levels are increased resulting in the increased clearance of drugs by these
enzymes e.g. remifentanil. Hepatic clearance is usually normal but may be impaired in liver
disease caused by obesity. Renal clearance is usually increased due to increased body
weight, increased renal blood flow and increased glomerular filtration rate. Renal clearance
may be impaired in renal disease caused by obesity related diseases, e.g. diabetes. Insulin
doses may be increased due to peripheral insulin resistance in type 2 diabetes caused by
obesity. Most answers were deficient in examples of drugs to illustrate the effects of obesity
on drug pharmacology.
Question 20
Question
What are drug enantiomers? (20% of marks). Explain the clinical relevance of enantiomers (60% marks). Give clinically relevant example (20% of marks)
Example answer
Enantiomers
A stereoisomer which has identical chemical formula and bond structure, but the relative positions of the functional groups in 3D space differ such that the molecules are not superimposable (they form mirror images of each other)
Named according to their absolute configurations in 3D space
R (rectus) atomic numbers descend clockwise
S (sinister) atomic numbers descend anticlockwise
Example
Ketamine is typically presented in a racemic mixture
However, R- is less effective and has a higher incidence of adverse effects compared to S+ ketamine enantiomer.
Relevance
Enantiomers, due to their different configurations in space, interact differently with receptors, transport proteins and enzymes > differing pharmacokinetics and dynamics
Pharmaceutics
Enantiopure preparations are more expensive (hence racemic mixtures more common)
Pharmacodynamics
Will interact with receptors differently > differing degrees of agonism/antagonism + also compete for receptors > variable effects (R-ibuprofen 100X more portent inhibitor COX than S ibuprofen)
Enantiopure preparations are more likely to include the most active or least toxic isomer (e.g. s-ketamine)
Pharmacokinetics
Absorption
No change in passive absorption
Active transport may favour one enantiomer over another (e.g methotrexate)
Distribution
Stereoselectivity in protein binding which will also affect the Volume of distribution and proportion of active drug (e.g. propranolol)
Metabolism
Stereoselectivity in metabolism due to varying degrees of interaction with enzymes (e.g. warfarin and CYP450)
Elimination
Stereoselectivity in elimination (e.g. ibuprofen)
Examiner comments
41% passed
Enantiomers refer to isomeric molecules with centres of asymmetry in 3 dimensions that are mirror images of each other but not superimposable. Enantiomers may be distinguished by the direction in which polarised light is rotated. Interactions involving weak drug-receptor bonds feature a dependence upon recognition of shape, i.e. stereochemical structure is often important. Frequently one enantiomer may bind to a given receptor more avidly than the other, thus pharmacodynamics, pharmacokinetics and toxicity may vary between enantiomers. Many drugs are supplied as racemic mixtures, the components of which have different activity. Clinically relevant examples that candidates could have mentioned, included bupivacaine, ropivacaine, ketamine and carvedilol.
2011 (1st sitting)
Question 14
Question
Describe the mechanisms of action and adverse effects of pulmonary vasodilators that are administered via the inhalational route.
Answer
Oxygen
A pulmonary vasodilator in hypoxic patients (reverses hypoxic pulmonary vasoconstriction)
MOA
Initial phase HPVC: Decreased O2 (hypoxia) > altered redox state in mitochondria of SM muscles > inhibition of K channels > depolarisation > Ca influx > vasoconstriction
Prolonged hypoxia: maintains HPVC through decreased NO release +release of endothelin derived vasoconstrictors
O2 therefore reverses this process of HPVC
Effects
RESP: improved oxygen saturations (may also improve DO2), decreased respiratory drive (minor), pulmonary toxicity (free radical generation), may worsen V/Q mismatch, absorption atelectasis, hypercapnoea (in chronic CO2 retainers)
CVS: decreased pulmonary vascular resistance (vasodilation) due to reversal of HPV, increased HR/SV/SVR in setting of hypoxia (via chemoreceptor reflex) > increased CO and BP, coronary vasoconstriction
Binds to prostacyclin receptor (IP receptor) > Activates GPCR > increases cAMP > decreased platelet activation and increased SM relaxation.
If given inhaled > local effects in regions of well ventilated alveoli only
Effects
RESP: pulmonary arterial vasodilation > improve V/Q matching + oxygenation in patients with ARDS if inhaled (goes to ventilated regions only), but may worsen it if given intravenously (goes to all pulmonary blood vessels > worsening shunt)
HAEM: inhibition of platelet aggregation > increased risk bleeding
CVS: flushing, hypotension, reflex tachycardia, decreased pulmonary vascular resistance and mPAP > decreased RV afterload (may improve CO in RHF)
CNS: headache, increased CBF
Examiner comments
Many candidates neglected to include oxygen which is also a drug with significant pulmonary vasodilating properties. Accurate detail concerning the receptor and second messenger effects of drugs was expected. The importance of V/Q matching and reduction in systemic effects via inhalational administration needed to be stated. Better answers included discussion of serious adverse effects such as methaemoglobinaemia, acute lung injury, systemic hypotension, rebound phenomena and heart failure.
Most candidates did reasonably well by including aspirin, ADP receptor blockade and glycoprotein 2b/3a blockade in their answers. The best approach to answer this type of question was to use a table with each anti-platelet agent within a column and headings for the rows such as mechanisms of action, adverse effects, mode of elimination and duration of action.
Common omissions included the irreversibility of the blockade of the platelet function by many of these agents, renal toxicity and bronchospasm as side effects of aspirin, bone marrow toxicity of ADP receptor blockers, and dipyridamole as an anti-platelet agent. Some candidates classified clopidogrel as a glycoprotein 2b/3a blocker incorrectly and thought clopidogrel has a relative short duration of action on platelet function because of its half-life. Clopidogrel as a prodrug requiring activation by cytochrome P450 and hence significant potential drug interactions were not mentioned by any candidates.
Decreased renal mass / nephrons with age > decreased GFR > reduced clearance > prolonged effects (e.g. vancomycin) or increased toxicity (e.g. gentamicin)
Decreased hepatic blood flow / tissue mass > impaired liver/GIT clearance of drugs (e.g. morphine)
Examiner comments
53% of candidates passed this question.
As the general population ages, and many elderly are admitted to intensive care units and/or
encountered during intensive care ward consultations, this topic is highly relevant. Unfortunately
candidate performance generally lacked sufficient depth and breadth in this area. Good answers
were expected to mention changes in body compartments (eg total body water, lean body mass
decrease, etc), consequences of changes in organ function (eg deteriorating glomerular filtration
rate, reduced liver blood flow, etc), alterations in protein levels and binding, increased likelihood of
drug interactions and the influence of disease states.
Question 24
Question
Classify anti-hypertensive agents by their mechanism of action with a brief outline of each mechanism and an example of a drug in each class.
Answer
Sympatholytic's
Class
Example
MOA
Alpha blockers
Prazosin
<math display="inline">\alpha</math>1 antagonist > arterial and venous vasodilation > ↓ SVR > ↓ BP
Beta blockers
Metoprolol
<math display="inline">\beta</math>1 antagonist > ↓ inotropy and ↓ chronotropy > ↓ BP
Centrally acting
Clonidine
Central <math display="inline">\alpha</math>2 agonist > ↓ SNS tone (via ↓ NA release) > ↓ BP
RAAS inhibitors
Class
Example
MOA
ACE inhibitors
Ramipril
Block the conversion of angiotensin I to angiotensin II by ACE > decreased AG2 > ↓ SVR and ↑ natriuresis > ↓ BP
ARBs
Candesartan
Same as ACEI (above) but blocks AG2 directly.
Calcium channel blockers
Class
Example
MOA
Dihydropyridine
Amlodipine
Blocks L-Type calcium channels in SM > ↓ intracellular Ca > vasodilation > ↓ SVR > ↓ BP
Non-dihydropyridine
Verapamil
Same as dihydropyridines, but additionally preferentially acts on cardiac cells > ↓ HR and ↓ contractility > ↓BP
Diuretics
Class
Example
MOA
Loop diuretic
Frusemide
Blocks to NK2Cl transporter in the aLOH> ↓ Na,K, Cl reabsorption > ↓ medullary tonicity + ↑ Na/Cl delivery to distal tubules > diuresis > ↓ BP. N.B Direct vasodilation effect - MOA unclear
Thiazide diuretic
Hydrochlorothiazide
Blocks Na/Cl cotransporter in DCT > ↓ Na+ and Cl- reabsorption > diuresis > ↓ BP
Potassium sparing diuretic
Spironolactone
Competitive aldosterone antagonist > ↓ Na reabsorption in DCT > diuresis > ↓ BP
Vasodilators
Class
Example
MOA
Nitrates
GTN
Dinitrated to NO > diffuses into SM > binds to guanylyl cyclase > ↑ GMP > ↓ intracellular Ca > vasodilation > ↓ BP
Hydralazine
Hydralazine
Not fully understood. Though to also activate guanylyl cyclase > ↑ GMP > ↓ intracellular Ca > arteriolar vasodilation > ↓ BP
Examiner comments
67% of candidates passed this question.
There are many valid lists that can be used as a template to answer this question. One such list might broadly classify antihypertensive agents into sympatholytic agents, vasodilators, calcium channel antagonists, renin-angiotensin inhibitors and diuretics. Within each of these categories are a variable number of sub classes, for example diuretics might include thiazides, loop diuretics and potassium sparing diuretics. A good answer would include such a listing with a brief description of the mechanism of action with respect to the antihypertensive effect and the name of a typical drug that acts in the manner described. Most candidates were able to generate such a list and populate it as required by the question, thus being rewarded with good marks. Poorer answers lacked any logical classification system and were merely a random list of antihypertensive drugs and their actions. Candidates are reminded that organisation within an answer helps in answering the question and achieving marks.
Outline the kinetic characteristics and the mode of action of digoxin (75% marks). List the cardiovascular effects of digoxin (25% marks).
Answer
Pharmacokinetics
Onset/duration
Onset; 2-3 hours (PO), 10-30mins (IV)
Duration of action: 3-4 days
Absorption
Well absorbed from GIT
80% oral bioavailability
Distribution
Protein binding ~25%
VOD 6-7L/kg
High lipid solubility
Metabolism
Minimal hepatic metabolism (15%)
Oxidation and conjugation
Active and inactive metabolites
Elimination
Renal elimination (70% unchanged)
Small amounts of faecal/biliary elimination <15%
T 1/2 = 48 hours
Not readily dialysable
Cardiovascular effects
Positive inotropy
Inhibits Na/K ATPase > Increased Na > impairs Na/Ca exchanger > increased intracellular Ca > increased inotropy > increased CO
Negative chronotropy and dromotropy
Increased PSNS release of ACh at M receptors > decreases SA node firing (chronotropy) + prolongs AV conduction (dromotropy) > increased diastolic filling time > increased preload > increased SV > increased CO + BP
Can also lead to bradycardia, AV block, bradyarrhythmia's
Increased excitability
Increases slope of phase 4 > enhances automaticity of atrial, junctional, ventricular tissue > arrhythmias
The Syllabus for the Primary examination describes an outline to be “Provide a summary of the important points.†Thus candidates were expected to briefly mention the fundamental pharmacokinetic characteristics (eg highly lipid soluble, well absorbed from small intestine, oral bioavailability of 60 - 90%, protein binding of 20 - 30%, volume of distribution, half life, etc) and mode of action. This was poorly done and candidates’ answers often lacked structure. The question outlines the distribution of marks, being 25% for listing cardiovascular effects. Thus candidates were expected to broadly list the important cardiovascular effects relating to mechanical (eg increase intensity of myocardial contraction, direct venous and arteriolar constriction, etc) and electrical ( increase phase 4 slope & automaticity, hyperpolarization, shortening of atrial action potentials, decrease AV conduction velocity and prolong AV refractory period, increase PR & QT intervals, dose and baseline autonomic activity dependent actions, etc).
Question 17
Question
Explain the difference and clinical relevance between zero and first order kinetics (60% marks). Give an example that is relevant to intensive care practice (40% marks)
Example answer
First order kinetics
A constant proportion of a drug is eliminated per unit time
Enzyme/elimination systems are working below their maximum capacity
Therefore, elimination is proportional to drug concentration
Increasing concentration of drug will increase elimination of drug
Exponential concentration per time graph
Most drugs eliminated in this way
Zero order kinetics
A constant amount of drug is eliminated per unit time
Enzyme/elimination systems are saturated/working at maximal capacity
Increasing concentrations will not lead to increase in elimination
Linear concentration vs time graph
The transition from first order kinetics to zero order kinetics is described in the Michalis-Menten equation
Only some drugs are eliminated this way
Example: phenytoin, ethanol, salicylates
Because of this, increasing concentrations > increased risk of toxicity
Phenytoin reaches the therapeutic range at the point at which it transitions from first to zero-order kinetics > very narrow therapeutic range > requires monitoring / dosage adjustment
Examiner comments
2008 (1st sitting)
Question
Question
Describe the role of the kidney in drug excretion and the factors affecting this. Briefly outline how you would alter the dosing of gentamicin in a patient with renal impairment
Example answer
Renal excretion/elimination
Principle mechanism of drug elimination
Renal elimination is a balance between glomerular filtration, tubular secretion and reabsorption.
Factors affecting glomerular filtration
GFR
Increased GFR = increased filtration = increased clearance of hydrophilic drugs
Drug size:
Increasing drug size = decreased renal clearance
Only drugs <7kDa (weight) or <30 Angstrom units (width) are able to pass the capillary BM
Protein binding
Only unbound drugs can pass the glomerular BM
Highly protein bound drugs are poorly filtered
Charge
Negatively charged molecules cannot readily pass BM (as it is also negatively charged)
- Diffuses into RBCs and reacts with Oxy-Hb to produce NO
- NO diffuses into cell > incr cGMP > decreased Ca > SM relaxation
Prodrug
- Dinitrated to produce active nitric oxide (NO).
- NO diffuses into smooth muscle cell > binds to guanylyl cyclase > increased cGMP > decreased intracellular Ca > SM relaxation > vasodilation
Effects
CVS: Arterial+venous vasodilation > decreased BP + afterload
Can develop tachyphylaxis (depletion of sulfhydryl groups)
Examiner comments
80% of candidates passed this question
It was expected candidates would address specific aspects of pharmacology such as action, mechanism of action, half life and duration of effect, route of administration, potential toxicity and special precautions. These agents lend themselves to comparison and contrast as several distinct similarities and differences exist and credit was given for highlighting these. Specific comments should include that both agents result in blood vessel dilation with extra credit given for detailing the differences in the balance of arterial versus venous effects between them. For both agents the effect is mediated through nitric oxide and it was expected candidates would identify that nitroprusside releases NO spontaneously and GTN requires enzymatic degradation with the resultant effects on smooth muscle mediated via c GMP. They are both short acting agents when used intravenously and require careful titration to measured blood pressure for effect. Extra credit was given for mentioning that routes other than IV are available for GTN (topical / oral) but not for nitroprusside. Comments on special precautions such as Nitroprusside should be protected from light and GTN given via non PVC giving sets gained additional marks. In addition to the well described adverse effects of each agent, it was expected candidates would mention the potential for cyanide toxicity with nitroprusside and extra marks were awarded for an indication of usual doses.
2007 (2nd sitting)
Question 2
Question
Outline the sites and mechanisms of action of diuretics. Give one example of drug acting at each site and list two side effects of each drug.
Example Answer
Site of action
Example
Mechanism of diuresis
Side effects
Entire
Mannitol
Freely filtered at glomerulus (but not reabsorbed). Acts osmotically to ↓ H2O reabsorption
- ↓ Na, K, Cl
- Hypotension, hypovolaemia
PCT
Acetazolamide
Inhibits carbonic anhydrase in PCT > ↓ reabsorption of filtered HCO3 + Na > ↑ tubular osmolality > diuresis
- Metabolic acidosis (↓ HCO3)
- ↓ Na, K, Cl
LOH
Frusemide
Binds to NK2Cl transporter in the thick ascending limb LOH > ↓ Na,K, Cl reabsorption > impairs counter current multiplier + ↓ medullary tonicity
Good answers to this question were those that had a tabular format to the structure of the answer — for example columns headed mechanism, sites, drug and side effects. Most common omissions were not to further describe how the different mechanisms of action of diuretics increased urine output, e.g. "disruption of the counter current multiplier system by decreasing absorption of ions from the loop of Henle into the medullary interstitium, thereby decreasing the osmolarity of the medullary interstitial fluid". There was often little mention of increased urine solutes and the effect the electro chemical effect had in promoting a diuresis. Examples of drugs were well done
Outline with examples the role of excipients in drug formulations.
Example answer
Excipient
Components of a drug preparation that do not exert the pharmacological effect
Function: assists with optimal delivery of the active ingredient
Ideally: nontoxic, inactive, and don’t interact with active ingredient
Preservatives
Prevent/inhibit growth of microorganisms in the drug preparation
Generally weak acids (pKa 4-5)
Example: benzyl alcohol
Antioxidants
Prevent/limit the degree of chemical breakdown due to oxidative reactions
Example: ascorbic acid
Solvents
A liquid (usually) substance which can dissolve another substance
Water is the most common solvent (most drugs are water soluble to an acceptable degree)
For non-water-soluble drugs, or drugs unstable in water, non-aqueous solvents are used (e.g. mannitol, propylene glycol)
Buffer
A solution consisting of a weak acid and its conjugate base
Maintains the pH of a drug preparation to maximise stability and/or maintain solubility
Example: acetic acid / sodium acetate
Emulsifying agents
Substances that stabilise emulsions which are typically unstable
Example: soya bean oil / egg lethicin in propofol
Diluents
Provide bulk and enable accurate dosing of potent ingredients
E.g. glucose, lactose
Binders
Bind tablet ingredients together for form/strength
Example: starches, sugars
Flavours
Added to increase compliance / ease of use
Example: aspartame
Colouring
Added for marketing purposes / compliance
E.g. beta caroteine
Coatings/film
Designed to make tablets easier to swallow, improve predictability of absorption, protect from environment e.g moisture
Example: cellulose for enteric coating to delay release of agent
Examiner comments
Not previously examined
Question b
Question
Describe the mechanism of action and effects of corticosteroid drugs with particular reference to asthma
Answer
Asthma
Asthma is an inflammatory condition of the airways characterised by airway narrowing, mucous secretion and expiratory airflow limitation.
Corticosteroids
Steroid hormones normally produced by the adrenal cortex
Two main classes of corticosteroids
Glucocorticoids (secreted from zona fasciculata and reticularis)
Mineralocorticoids (secreted from zona glomerulosa)
Glucocorticoids are used in the treatment of asthma
Systemic: Prednisone, Hydrocortisone
Inhaled: Beclomethasone, Budesonide
Note: prednisone and hydrocortisone also have some mineralocorticoid effect
Glucocorticoids
Mechanism of action
Lipid soluble hormone > crosses cell membrane > binds to intracellular steroid receptors > translocate to nucleus > alters gene transcription > metabolic, anti-inflammatory & immunosuppressive effects in tissue-specific manner
The anti-inflammatory process is mediated by suppression of phospholipase A2 > decreased arachidonic acid > decreased PGs, TXA2, Leukotrienes
Inhaled steroids (e.g. budesonide) at regular dosage tend to have only respiratory (local) effects, whereas systemic glucocorticoids (e.g. hydrocortisone, prednisone) exhibits effects at all sites.
Effects on asthma
RESP
Reduced airway oedema > bronchodilation
Increased SM responsiveness to catecholamines and B2 agonists > bronchodilation
Bronchodilation + decreased mucous secretion > improved ventilation + oxygenation > decreased work of breathing
CVS
Increased BP (Due to mineralocorticoid effect on kidneys (increased H2O reabsorption) and increased alpha adrenergic responsiveness to endogenous catecholamines)
Other effects of systemic steroids
RENAL
Increased fluid reabsorption (Due to mineralocorticoid effect on kidneys > increased Na/H20 reabsorption in DCT > increased BP, oedema)
Metabolic
Hyperglycaemia (Due to increased gluconeogenesis, protein catabolism, lipolysis)
Adrenal suppression (Due to negative feedback on the pituitary (inhibits ACTH) and hypothalamus (inhibits CRH))
Hepatic metabolism (90%) via CYP450 mechanisms to active and inactive metabolites. 10% unchanged
Elimination
Renal elimination of active and inactive metabolites
Dialysable
T 1/2 = 6-12 hours (longer in children)
Special points
Therapeutic concentration 10-20mg/ml
Examiner comments
Not previously examined
Question dnus
Question
Outline the pharmacology of metoclopramide.
Answer
Name
Metoclopramide
Class
Antiemetic / Prokinetic
Indications
- Nausea and vomiting
- Prokinetic
Pharmaceutics
Clear colourless solution (5mg/ml).
Tablet (10mg)
Routes of administration
IV, PO, IM
Dose
10mg TDS (adults) for short duration (max 5 days)
Pharmacodynamics
MOA
Central D2 antagonism at chemoreceptor trigger zone > reduced afferent input to vomiting centre in medulla
Effects
GIT: Anti-emetic, Prokinetic (acceleration of gastric emptying)
CNS: EPSE (akathisia, dystonia, tardive dyskinesia) in children, drowsiness, dizziness, headache, worsening of Parkinson symptoms
CVS: arrhythmias
Pharmacokinetics
Onset
Tmax < 1 hour (PO), <15 mins (IV)
Absorption
PO bioavailability 80%
Distribution
VOD = 3L / Kg
Protein binding 30%
Metabolism
Minimal hepatic metabolism (conjugation)
Elimination
Renal elimination (85%)
Active and inactive metabolites
T 1/2 = 4 hrs
Special points
- Contraindicated in pheochromocytoma (precipitates pheo crisis), Parkinson's (Blocks Dopamine receptors), GI obstruction/perforation (prokinetic), avoid in children <20 years old (risk of EPSE)
