2020A
2020 (1st sitting)
Question 1
Question
Describe the carriage of carbon dioxide in blood.
Example answer
Overview
- CO2 is constantly produced as a by-product of metabolism and needs to be cleared
- CO2 content of blood
- Mixed venous: 52mls/100mls blood, at PaCO2 of ~45mmHg
- Arterial: 48mls/100mls blood, at PaCO2 of ~40mmHg
- CO2 is transported in three main forms in the blood
- Dissolved
- As bicarbonate
- In combination with proteins (carbamino compounds)
Dissolved CO2
- Accounts for
- ~5% of the total carbon dioxide in the blood
- ~10% of the CO2 evolved by the lung
- The amount dissolved is proportional to the partial pressure (Henry's Law)
- 20x more soluble than O2, so dissolved CO2 plays a more significant role in transport
Bicarbonate
Accounts for
~90% of the carbon dioxide in the blood
~60% of the CO2 evolved by the lung
Bicarbonate is formed by the following sequence
<math display="block">CO_2 + H_{2}O \leftrightarrow H_{2}CO_{3} \leftrightarrow H^+ + HCO_3^-</math>Process
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.
Online resources for this question
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Question 2
Question
Describe the pharmacology of glyceryl trinitrate (GTN)
Example answer
| Name | Glyceryl trinitrate (GTN) |
|---|---|
| Class | Organic nitrate |
| Indications | Hypertension, acute pulmonary oedema, angina, ACS/LV failure, |
| Pharmaceutics | Clear liquid (IV), Patch (transdermal), tablet (SL), spray (SL) |
| Routes of administration | Sublingual, intravenous, transdermal, PO |
| Dose | 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 |
| Effects | CVS: systemic vasodilation (preferentially venodilation, coronary arterial dilation) > decreased SVR > decreased BP + VR, decreased myocardial O2 consumption (decreased VR > decreased preload), reflex tachycardia CNS: Increased CBF > inc ICP, headache RESP: Bronchodilation (weak), decreased PVR OTHER: flushing, methaemaglobinaemia |
| Pharmacokinetics | |
| Onset | 1-3 mins (SL), <1 min (IV), Patch variable. |
| Absorption | Oral bioavailability <5% (hepatic high first pass effect) Sublingual spray 40% Sublingual tablet 60% |
| Distribution | 60% protein bound. Vd 3L/kg |
| Metabolism | Hydrolysis Site: liver + RBC cell wall + vascular cell walls. Active metabolites |
| Elimination | Renal T 1/2 B = 5 minutes (parent compound). |
| Special points | 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.
Online resources for this question
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Question 3
Question
Outline the potential adverse consequences of blood transfusion.
Example answer
Immunological (acute < 24 hours)
| Adverse event | Incidence | Mechanism |
|---|---|---|
| Acute haemolytic transfusion reaction | 1 : 75,000 (Death 1:2 mil) |
E.g. ABO incompatibility. Immunological destruction of transfused cells (Type II hypersensitivity). |
| Febrile non-haemolytic transfusion reaction | ~1% | Cytokine release from stored cells causing a mild inflammatory reaction with recipient alloantibodies |
| Mild allergic reactions (e.g. urticaria) | ~1-5% | Hypersensitivity to plasma proteins in the transfused unit |
| Severe allergic reactions (i.e. anaphylaxis) | ~ 1 : 50,000 | Type I hypersensitivity reaction to plasma protein in transfused unit |
| Transfusion related acute lung injury (TRALI) | Variable | Donor plasma HLA activates recipient pulmonary neutrophils, causing fever, shock, and non-cardiogenic pulmonary oedema |
Immunological (delayed > 24 hours)
| Adverse event | Incidence | Mechanism |
|---|---|---|
| Delayed haemolytic transfusion reaction | 1: 5,000 | 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. |
| Others | Variable | Hypothermia, coagulopathies, electrolytes disturbance, metabolic derangements |
Non-immunological (delayed > 24 hours)
| Adverse event | Incidence | Mechanism |
|---|---|---|
| Iron overload | Rare (unless massive transfusion e.g. >20 units) | 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.
Online resources for this question
- Part One, LITFL
- Lifeblood, red cross blood service
- Jennys Jam Jar
- CICM Wrecks
- Deranged Physiology
- Ketamine Nightmares
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Question 4
Question
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.
Online resources for this question
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Question 5
Question
Outline the mechanisms of antimicrobial resistance (50% of marks). Briefly outline the pharmacology of ciprofloxacin (50% of marks).
Example answer
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 resistance to carbapenems due to reduction in porins
- Active efflux of drug
- Efflux pumps > extrude antibiotics e.g. fluoroquinolone resistance
- Decrease permeability
- Alter antibiotic target site
- e.g. VRE - Alteration to Peptidoglycan binding site protein, reducing affinity of drug.
- Modification / inactivation of drug
- E.g. ESBL and penicillins/cephalosporins whereby b-lactamases hydrolyse B-lactam rings
- Modification of metabolic pathways
- E.g. Bactrim resistance. Metabolic pathways bypass site of antibiotic action
| Name | Ciprofloxacin |
|---|---|
| Class | Quinolone |
| Indications | Prostatitis, complicated UTIs, bone/joint infections |
| Pharmaceutics | Oral tablet, light-yellow power for injection (water diluent) |
| Routes of administration | IV, PO |
| Dose | 250-750mg BD (PO), 200-400mg BD/TDS (IV) |
| Pharmacodynamics | |
| MOA | Bactericidal; inhibit bacterial DNA synthesis by blocking DNA gyrase and topoisomerase IV. |
| Spectrum | Broad spectrum (GN+ MSSA). Effective against pseudomonas + anthrax (lol) Effective against some atypicals (legionella). |
| Side effects | GIT: nausea, vomiting CNS: dizziness, headache |
| Pharmacokinetics | |
| Onset | 1-2 hours (PO) for peak effect. Immediately (IV) |
| Absorption | Oral bioavailability 70% |
| Distribution | 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.
Online resources for this question
- CICM Wrecks
- Jennys Jam Jar
- AMH/MIMS
- Part One, LITFL
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Question 6
Question
Outline how the respiratory system of a neonate differs from that of an adult.
Example answer
Anatomical differences in neonates (with respect to adults)
- Head
- Larger head and occiput
- Smaller mandible
- Larger tongue, tonsils, adenoids.
- Neck
- Shorter neck with higher laryngeal position
- Larger, less rigid epiglottis
- Larynx/trachea/bronchi
- Shorter, narrower and softer trachea
- Main Bronchi angle equal L-R for neonate (adults right is more vertical)
- Reduced bronchial smooth muscle > less bronchospasm (but bronchodilators less effective)
- Alveoli
- Fewer (and more immature) alveoli
- Reduced type 1 muscle fibres in diaphragm (25% neonates, 55% in adults) - more susceptible to fatigue
Physiological differences in neonates (with respect to adults)
- Volumes/capacities
- Similar FRC (30ml/kg), and TV (7mls/kg) to adults
- Lower vital capacity (45mls/kg) and TLC (65mls/kg)
- Increased minute ventilation (generated by increased RR, as TV proportionally similar)
- Increased physiological deadspace (3mls vs 2 mls)
- Increased closing capacity > increased shunt
- Compliance
- Increased chest wall compliance (proportionally more cartilage)
- Decreased lung compliance (less surfactant)
- Resistance
- Respiratory resistance is increased at birth: bronchi are smaller and lung volumes are smaller
- Mechanics
- Obligate nose breathers
- More susceptible to fatigue (Reduced type 1 muscle fibres in diaphragm)
- Increased work of breathing overall (increased MV, increased dead space, increased shunt)
- Gas exchange
- Increased oxygen consumption (6mls/kg/min)
- Increased shunt (10-25%, due to patent ductus arteriosus)
- Foetal haemoglobin = increased oxygen affinity (left shift oxy curve)
- Control
- 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.
Online resources for this question
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Question 7
Question
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
- <math display="inline">SVR = { 8l. \eta \over \pi r^4}</math>
- 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
- Temperature
- Heat causes vasodilation > decreased SVR (and vice versa)
Regional/local control of vessel radius
- Myogenic autoregulation
- e.g. brain, kidneys, can alter vessel radius via myogenic means. Less important peripherally.
- Incr. pressure > incr. stretch > release of vasoactive mediators > constriction > increased SVR
- Metabolic autoregulation
- e.g. brain, coronary vasculature
- Decreased oxygen delivery / increased utilisation > increased metabolites (CO2, H, lactate, NO, adenosine) > vasodilation > decreased SVR
Examiner comments
21% of candidates passed this question.
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.
Online resources for this question
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Question 8
Question
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)
- Glucose is converted to pyruvate via glycolysis
- 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
- Emerging evidence that lactate
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.
Online resources for this question
- Jenny's Jam Jar
- CICM Wrecks
- Also used Ohs, LITFL, random websites
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Question 9
Question
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
- Oral
- 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
- Volume of distribution
- 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)
- Liver
- 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
- Renal
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.
Online resources for this question
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Question 10
Question
Compare and contrast the pharmacology of noradrenaline and vasopressin.
Example answer
| Name | Noradrenaline | Argipressin |
|---|---|---|
| Class | Endogenous catecholamine | Endogenous nonapeptide |
| Indications | Vasopressor (Hypotension/shock) | Platelet dysfunction (vWD), hypotension/shock (catecholamine sparing), CNS diabetes insipidus |
| Pharmaceutics | Clear solution. 1:1000. Brown ampule (prevent light oxidation). Diluted in dextrose. | Clear colourless solution |
| Routes of administration | IV only (central vein) | IV infusion (central vein) for vasopressor support. Given IN/SC for other indications. |
| Dose | Infusion titrated to effect (generally 0 - 0.5 mcg/kg/min) | 2.4 units/hr (for vasopressor support) - At lower doses has predominant V1 activity, V2 activity at higher doses |
| pKA | ||
| Pharmacodynamics | ||
| MOA | Predominately Alpha 1 agonism. Some beta adrenergic receptor agonism. a1 > B1 > B2 | Physiologically secreted by PVN of hypothalamus > stored in posterior pituitary > secreted in response to hypovolaemia + increased osmolality → V1 receptor (blood vessels) agonism > Vasoconstriction > increased SVR > increased BP |
| Effects | CVS: peripheral vasoconstriction > increased SVR > inc. BP, reflex bradycardia, increased afterload (from SVR) > decreased CO (minor), increased myocardial O2 consumption, no sig. change in dromotropy, lusitropy or inotropy CNS: decreased CBF (depending on BP), headache |
CVS: ACS, angina, arrhythmias HAEM: Excessive platelet aggregation / thrombosis |
| 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 |
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.
Online resources for this question
Similar questions
- 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.
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Question 11, 2014 (1st sitting)
Question 14, 2016 (2nd sitting)
Question 12
Question
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.
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Similar questions
Question 24, 2012 (1st sitting)
Question 12, 2015 (1st sitting)
Question 17, 2017 (2nd sitting)
Question 13
Question
Explain the control of breathing
Example answer
Normal respiration
- 12-20 / min
- Normal tidal volumes ~6-8mls/kg (~500mls in 70kg adult)
- Normal minute ventilation ~6-10L/min
Voluntary control of respiration
- Mediated via the cerebral cortex via the corticospinal tracts and motor neurons of the muscle of respiration
Involuntary control of respiration
- Adjusts ventilation to adapt to the needs of the body
Sensors + afferents
- Peripheral chemoreceptors
- Located in carotid and aortic bodies
- Stimulated by fall in PaO2, rise in PaCO2, or fall in pH
- Afferents CN IX (carotid body) and CN X (aortic body)
- Central chemomreceptors
- Located at ventral medulla near the respiratory centre
- Detects change in CSF pH (due to CO2 diffusion across BBB)
- Mechanoreceptors
- Slow stretch receptors in the bronchial and lung tissue
- Activated by stretch
- Afferent is CN X
- Other inputs:
- Temperature (thalamus)
- Emotion (limbic system)
- Hormones (adrenaline)
- Lung water (J receptors in the lung)
- Baroreceptor reflex
Integrator/controller + efferents
- Respiratory centre in the medulla and pons
- Nucleus retroambiugualis (controls expiratory muscle group via UMN)
- Nucleus parambigualis (controls inspiratory muscle group via UMN)
- Nucleus ambigualis (pharyngeal muscle dilator function)
- Pre-botsinger complex (respiratory pacemaker > phrenic nerve)
- Pontine respiratory group (prevents over expansion of the lung)
Effectors
- Muscles of respiration
- Pharyngeal muscles - dilate airway
- Laryngeal muscles - abduct vocal cords
- External intercostals - elevate ribs, move sternum forward > increase AP + lateral diameter thoracic cavity
- Diaphragm = main inspiratory muscle > increases intrathoracic volume
- Accessory muscles = SCM, pecs, scalene, abdominal muscles
Examiner comments
53% of candidates passed this question.
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.
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Question 21, 2013 (1st sitting)
Question 2, 2015 (1st sitting)
Question 13, 2015 (2nd sitting)
Question 14
Question
Describe the pharmacology of frusemide.
Example answer
| Name | Furosemide |
|---|---|
| Class | Loop diuretic |
| Indications | Oedema/fluid overload, renal insufficiency, hypertension |
| Pharmaceutics | Tablet, clear colourless solution (light sensitive), |
| Routes of administration | IV, PO, |
| Dose | Varies (~40mg daily commonly used for well patients, can be sig. increased) |
| pKA | 3.6 (highly ionised; poorly lipid soluble) |
| Pharmacodynamics | |
| MOA | Binds to NK2Cl transporter in the thick ascending limb LOH, leads to decreased Na,K, Cl reabsorption > decreased medullary tonicity + Inc Na/Cl delivery to distal tubules > decreased water reabsorption > diuresis |
| Effects | Renal: diuresis CVS: hypovolaemia, arteriolar vasodilation + decreased preload (=mechanism for improvement of dyspnoea before diuretic effect) |
| Side effects | CVS: hypovolaemia, hypotension Renal/metabolic: Metabolic alkalosis, LOW Na, K, Mg, Cl, Ca, increased Cr |
| Pharmacokinetics | |
| Onset | 5 mins (IV), 30-60 mins (PO), Effect lasts 6 hours. |
| Absorption | Bioavailability varies person-person (40-80%) |
| Distribution | Vd = 0.1L/Kg, 95% protein bound (albumin) |
| Metabolism | < 50% metabolised renally into active metabolite |
| Elimination | Renally cleared (predominately unchanged). T1/2 ~90 mins. |
| Special points | Deafness can occur with rapid 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.
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- Question 20, 2013 (1st sitting)
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Question 15
Question
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.
<math display="block">{Bioavailability} = \frac{AUC_{oral}}{AUC_{IV}}</math>
Factors influencing bioavailability
- Preparation of the drug
- Preparation (e.g. solution > capsule > tablet > coated tablet)
- Drug properties
- Molecular size (increase = decreased absorption)
- Degree of ionisation (non ionised - increased bioavailability)
- Lipid solubility (increased solubility = increased bioavailability)
- Route of administration
- Oral, transdermal, Subcutaneous, intramuscular, intranasal, inhaled etc.
- Drug interactions
- Drugs/food may interact/inactivate/bind to the drug
- e.g. absorption of tetracyclines reduced with concurrent administration of calcium such as in milk
- Patient factors
- Oral: Malabsorption syndromes (e.g. coeliac disease), gastric stasis (e.g. postop),
- IM/SC/Topical: Degree of tissue perfusion
- Pregnancy - alters gastric pH, intestinal motility
- 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.
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- Question 22, 2017 (2nd sitting)
Question 16
Question
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
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- Question 22, 2007 (1st sitting)
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Question 17
Question
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
Metabolism
- Morphine
- Metabolised hepatically (hepatic insufficiency - prolonged effect)
- Active metabolites (accumulate in renal failure - prolonged effect)
- Fentanyl
- Metabolised by liver (thus hepatic insufficiency = prolonged effect)
- Does not have active metabolites
Lipid solubility
- Morphine = poor lipid solubility = prolonged CNS effect
- 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.
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- Question 16, 2011 (1st sitting)
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Question 18
Question
Describe the respiratory changes that occur throughout pregnancy
Example answer
Anatomical changes
Diaphragm
Ascends progressively (up to 4cm) throughout pregnancy due to mass effect from the foetus
Chest wall
Increased AP + Lateral chest wall diameters
Thoracic circumfrence increases
Due to effect of relaxin
Increased oropharyngeal oedema (increased oestrogen)
Lung volumes
- Lung volume changes occur after trimester 1
- Mostly due to mass effect of pregnancy
- TLC decreases ~5%
- FRC decreases ~20%
- IC increases by 10%
- FRC decreased by 20%
- No change to closing capacity
Breathing + Mechanics
- Minute ventilation
- 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.
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- Question 4, 2014 (1st sitting)
Question 19
Question
Discuss the determinants of venous return to the heart.
Example answer
Venous return
- Rate of blood flow back to the right atrium
- In healthy state: venous return = cardiac output (else pathological pooling of blood occurs)
- Can be defined by
- VR = MSFP - RAP / resistance to venous return
- Therefore factors effecting venous return are those that affect
- MSFP
- RAP
- Resistance to venous return
- Cardiac output
Cardiac output
- Increased CO = increased venous reutn
- CO is effected by
- Afterload (reduced afterload = increased cardiac output = increased VR)
- Contractility (increased contractility = increased CO = increased VR)
MSFP
- Normally ~7mmHg
- Increased MSFP = increased VR
- Affected by venomotor tone and blood volume
- Increased VR (= increased blood volume and increased venomotor tone)
RAP
- Increased RAP = reduced driving pressure = reduced venous return
- Factors which increase RAP
- Positive intrathoracic pressure (e.g. PPV)
- Reduced pericardial compliance (e.g. effusion)
- Reduced RA compliance/contractility (e.g. AF)
- TVR
Resistance to venous return
- Increased RVR = reduced VR (due to ohms law)
- Factors effecting RVR
- Autonomic tone
- Intrabdominal pressure
- IVC Obstruction (e.g. pregnancy) reduces VR
- Posture (decreased VR with erect posture)
- Vasoactive drugs
- skeletal muscle pump
Examiner comments
67% of candidates passed this question.
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.
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- Question 6, 2018 (2nd sitting)
Question 20
Question
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.
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