Show the model answerAttempt it first — that is what makes it stick
What earns the marks10 marks
| (a) Pharmacokinetics only | 6 marks. No marks were awarded for pharmacodynamic properties, which some candidates included |
|---|---|
| (a) Volume of distribution first | The critique names it before anything else, and asks for the significance of the large volume, not the number alone |
| (a) Say why the CSHT matters | Many did not address its importance, or explain why a relatively short context-sensitive half-time during prolonged infusion suits TIVA |
| (a) The metabolite is active | 4-hydroxypropofol has about one-third of propofol's hypnotic activity. Several candidates stated propofol has no active metabolite |
| (a) Sites of metabolism, plural | Hepatic and extrahepatic, and the nature of the metabolite, were all expected |
| (a) Not the modes of TCI | No marks were awarded for explaining the various modes of target-controlled infusion |
| (b) Kinetic and dynamic | 4 marks, and this part is the mirror image of (a): both were required here |
| (b) Advantages and precautions | Both were asked for. An answer made only of cautions is half the part |
| (b) Reduced clearance and metabolism | Many did not address it, or the prolonged effect and delayed recovery that follow |
| (b) Ageing related to administration | How the haemodynamic changes influence dosing, bolus requirements and the choice of mode |
6 marks
The desirable pharmacokinetic features of propofol for TIVA
| Feature | The figure | The pharmacology behind it | What it means at the bedside |
|---|---|---|---|
| Large volume of distribution | About 4 L/kg, the largest of the induction agents. Steady state 2 to 10 L/kg, or 150 to 700 L, against a central compartment of only 6 to 40 L | A steady-state volume many times total body water is the signature of extensive tissue uptake rather than a real anatomical space. The drug leaves the plasma into muscle and then fat far faster than it is cleared | The plasma concentration falls steeply after every increment, so a target is reached and held by a modest infusion rate rather than a large one. The same fact is why the terminal half-life is long and tells you nothing useful |
| High lipid solubility, almost no ionisation | pKa 11, so essentially entirely unionised at pH 7.4. 98% protein bound, leaving 1 to 2% free | The free unionised fraction is what crosses the blood–brain barrier, and it does so on the first pass. Lipophilicity is not a separate property from the large volume above; it is its cause | The available fraction does not move with the patient's acid–base state, unlike thiopentone at pKa 7.6. Against that, a drug 98% bound has a free fraction sensitive to albumin, so the hypoalbuminaemic patient needs less for the same effect |
| Onset within one arm–brain circulation | Hypnosis after 2.5 mg/kg in one arm–brain circulation, peak effect at 90 to 100 seconds. ED50 for loss of consciousness 1 to 1.5 mg/kg | The brain sits inside the central compartment, and effect-site equilibration is fast enough that plasma and effect concentrations separate by only one to two minutes | One agent induces and maintains, so there is no gap between an induction drug wearing off and a maintenance agent taking hold. A change of target shows as a change in depth within a couple of minutes, so it can be titrated against surgical stimulus in real time |
| Redistribution | Initial distribution half-life 2 to 8 minutes, or 1 to 8 minutes in three-compartment analyses; slow distribution 30 to 70 minutes | Movement down a concentration gradient from the central compartment into muscle, then fat. No drug has been eliminated at this stage; it has only moved | This is what ends a single bolus, and it is emphatically not what ends an infusion. Once the peripheral compartments have filled the gradient is gone, redistribution can no longer clear the plasma, and a second bolus therefore lasts longer than the first |
| Three-compartment behaviour | A small central compartment with fast and slow peripheral compartments, and a clearance term on the central one only | The concentration-time curve is regular enough to be fitted by a model and solved forward in time, which is not true of every drug | Target-controlled infusion becomes possible at all, so a concentration can be set and held rather than chased with repeated boluses. The existence of validated adult models is the mark here; how their targeting modes differ is not |
| Very high clearance | 1.5 to 2.2 L/min, or 30 to 60 mL/kg/min, against a hepatic blood flow of about 1.5 L/min. Hepatic extraction ratio about 90% | An extraction ratio near unity makes clearance flow-limited: the liver removes almost everything presented to it, so delivery rather than enzyme activity sets the rate. A clearance at or above liver blood flow cannot be produced by the liver alone | Clearance tracks cardiac output. Anything that lowers output raises the concentration for an unchanged infusion rate, and propofol lowers output itself, so doubling the dose can more than double the concentration. In haemorrhagic shock concentrations rise about 20% until decompensation, then steeply |
| Metabolism at more than one organ | Renal metabolism up to 30% of clearance; extrahepatic metabolism up to 40% in total; a 20 to 30% fall in concentration measured across the pulmonary circulation | Confirmed directly rather than inferred: metabolites appear during the anhepatic phase of liver transplantation, with no liver in circuit at all. The kidney is the principal extrahepatic site and the lung contributes on first pass | Offset does not depend on any one organ, so no significant dose adjustment is needed in hepatic disease. Renal impairment does not prolong the anaesthetic either, because it is the inactive conjugates and not the parent drug that need excreting |
| Propofol inhibits CYP3A4 | A blood concentration of 3 μg/mL reduces CYP3A4 activity by about 37%. Midazolam in turn reduces propofol's own clearance from 1.94 to 1.61 L/min, and with midazolam and alfentanil together propofol concentrations rise by 20 to 30% | Competitive inhibition, so it appears almost immediately rather than over days as enzyme induction would. The interaction runs in both directions between propofol and the co-administered drugs of a TIVA technique | The drugs given alongside propofol in a total intravenous technique are the ones whose concentrations it alters, and which alter its own. Expect a co-induction combination to produce higher concentrations than either agent alone predicts, and titrate accordingly |
| A context-sensitive half-time that stays workable | 10 minutes after a 1-hour infusion, 24 after 4 hours, and still only 38.1 after 8 hours | The peripheral compartments approach equilibrium while clearance stays high, so the amount returning to the plasma when the infusion stops rises far more slowly than the duration of the infusion does | The feature the whole technique rests on. A four-hour case does not cost four times the wake-up of a one-hour case, so a long operation remains a reasonable indication for TIVA rather than an argument against it |
| A terminal half-life that should be quoted and then dismissed | 5 to 12 hours, and quoted as high as 23.5 hours, rising towards 60 hours if sampling continues beyond 24 hours | It measures slow release from fat long after the concentrations have ceased to matter, which is why the figure depends mostly on how long the study kept sampling | Quoting it and stopping there answers a different question. Naming the three half-lives and saying which one governs waking is the discriminating point, and the one that governs waking is the row above |
Where it is metabolised, and by what
The critique asked for the various sites of metabolism, hepatic metabolism and the nature of the metabolite. That is three separate things, and the pathway below carries all three.
The metabolic pathway, with the enzymes named
Two routes leave the parent drug, and the split is roughly 70 to 30
Move the infusion duration and read all six half-times at once
Context-sensitive half-time is the time for the plasma concentration to fall by half after an infusion stops, and context is how long the infusion ran. It is not the elimination half-life, and steady state is not part of the definition — an infusion can be stopped at any time. Drag the control and watch six agents separate: at ten minutes they are nearly indistinguishable, and by eight hours thiopentone has left the axis while etomidate has barely moved.
Two things set the shape of each curve. How high it rises is the ratio of distribution clearance to elimination clearance: if drug leaves the plasma into tissue much faster than it is eliminated, a reservoir accumulates and is handed back when the infusion stops. How long it keeps rising is the size and speed of the deep compartment — once that compartment is full, the curve plateaus.
Thiopentone and diazepam leave the axis because neither reaches a plateau inside eight hours. Thiopentone additionally saturates its own metabolism at high dose, so an infusion moves from first-order towards zero-order handling — a second reason its offset lengthens that the other agents do not share.
| Infusion duration | Context-sensitive half-time | What that means for the end of the case |
|---|---|---|
| 30 minutes | About 7.2 minutes | Barely different from a bolus. Recovery is still largely a redistribution event |
| 1 hour | About 10 minutes | The peripheral compartments have begun to fill, and the figure has roughly tripled from its value at time zero. Still short enough that the infusion can be stopped at skin closure |
| 2 hours | About 14.9 minutes | Doubling the case has added only about five minutes. This is the flatness that the whole technique depends on |
| 4 hours | About 24 minutes | Four times the duration for roughly twice the half-time. Worth stopping or reducing the target a little earlier, but not a reason to change technique |
| 6 hours | About 31.1 minutes | Still under half an hour. Compare thiopentone, whose curve has left the 150-minute axis entirely well before this point |
| 8 hours | About 38.1 minutes | The figure usually quoted, and the one worth memorising: under 40 minutes after a full working day of infusion |
The shape of that column is the argument, not any single number in it. An eightfold increase in infusion duration produces less than a fourfold increase in the half-time, because the peripheral compartments approach equilibrium while clearance stays high. Saying that sentence, rather than quoting 40 minutes and stopping, is what the critique records as missing.
Commonly lost: No marks were awarded for discussing pharmacodynamic properties, which some candidates included. The antiemesis, the obtunded airway reflexes, the fall in cerebral metabolic rate and the cardiovascular profile are all true, all creditable in other years, and all worth nothing here. The word in the stem is pharmacokinetic.
Commonly lost: No marks were awarded for explanations of the various modes of target-controlled infusion. That the drug can be modelled is a pharmacokinetic property and belongs in the answer; how plasma-site and effect-site targeting differ, and how Marsh differs from Schnider, is a description of the pump rather than of the drug, and it consumed time this question paid nothing for.
4 marks
Pharmacological considerations when giving TIVA to an elderly patient
| Change | Mechanism | Effect on TIVA | What you do |
|---|---|---|---|
| Smaller central compartment | Reduced cardiac output. The same bolus is diluted into a smaller volume | A higher peak plasma concentration from an unchanged dose, and therefore a deeper effect and a larger fall in blood pressure | Reduce the induction dose and the initial target |
| Reduced clearance | Reduced cardiac output and reduced hepatic blood flow. Propofol has an extraction ratio near 90%, so its clearance is flow-limited and follows delivery down | The dose needed to hold a given concentration falls, and the concentration falls more slowly when the infusion stops: prolonged effect and delayed recovery | Reduce the maintenance infusion rate or target as well as the bolus. This is a separate decision from the induction dose and was the one most often missed |
| Prolonged circulation time | Reduced cardiac output lengthens arm–brain time | Onset is slower even though the peak concentration is higher, so the two changes pull in opposite directions | Inject slowly and wait before repeating. The classic error is a second dose given before the first has arrived |
| Altered body composition | Total body water and lean body mass fall; fat rises as a proportion of body weight | The volume of distribution of a lipophilic drug rises, so the terminal decline is slower and the context-sensitive half-time after a long case is longer than the figure quoted in part (a) | Expect a longer wake-up after a long case, and plan the end of the infusion earlier |
| Weight is a poor guide to dose | A given weight in an elderly patient represents less lean mass and more fat than the same weight in a young one | A weight-scaled regimen overestimates the central compartment and overdoses the patient | Titrate to effect rather than to the number the pump displays, and use depth-of-anaesthesia monitoring where a neuromuscular blocking drug is also being given |
| Change | Mechanism | Effect on TIVA | What you do |
|---|---|---|---|
| Increased cerebral sensitivity | Falling neuronal density, receptor number and neurotransmitter concentration | Increasing age lowers the propofol concentration required for loss of consciousness, so the same target produces a deeper plane. This is additional to the kinetic changes, not a restatement of them | Set a lower target concentration, and expect the clinical endpoint at a number that would be inadequate in a young patient |
| Hypnosis arrives on time; the hypotension does not | The onset of the electroencephalographic effect is largely independent of age, but the onset of the fall in arterial pressure is roughly twice as slow and slows further with age | The patient is asleep before the blood pressure has finished falling, so the haemodynamic consequence of a dose is not yet visible when the decision to give more is taken | Wait longer than feels necessary before topping up, and treat the pressure you will have in two minutes rather than the one on the screen |
| Blunted baroreflex and reduced β-responsiveness | Reduced baroreceptor sensitivity and post-receptor signalling, with α-adrenoceptor responsiveness relatively preserved | The compensatory tachycardia that should defend the pressure does not appear, so propofol's vasodilatation is not self-limiting | Have a direct-acting vasoconstrictor drawn up. Phenylephrine or metaraminol is generally more effective than ephedrine |
| Stiff ventricle and stiff arteries | Reduced ventricular compliance with increased arterial stiffness and greater dependence on preload and atrial contraction | Vasodilatation and loss of sinus rhythm are both poorly tolerated, and the fall in venous return is amplified | Give fluid as tolerated before and during induction, and correct hypovolaemia before the infusion rather than after the pressure falls |
| Additive effect of a concurrent opioid | The opioid deepens the vasodilatation and removes the sympathetic drive that would oppose it | Older and sicker patients develop more profound hypotension, especially when propofol is combined with an opiate, and bradycardia becomes more likely | Reduce both drugs, not one. Propofol and remifentanil are synergistic, so raising the opioid target allows the propofol target to come down |
Why the same bolus does more harm in an older patient
Three consequences, in three different directions
Commonly lost: Many candidates did not address reduced drug clearance and metabolism in the elderly, which can lead to prolonged drug effects and delayed recovery. Reducing the induction dose is the easy half and nearly everyone wrote it. Naming the two proportionalities separates the halves in one line: the bolus scales with the central compartment volume, which is smaller, and the maintenance rate scales with clearance, which is lower. Two doses, two parameters, two reasons, and the second was the one left out.
Commonly lost: Candidates scored poorly overall, as many provided only superficial answers to both parts. Ten marks across two parts is roughly eighteen minutes. A four-mark part is not a footnote to a six-mark one, and on the evidence of this sitting the four-mark part is where the time was lost.
If this came up in the viva
Viva points
Why is propofol suitable for TIVA?
Answer
Its CSHT does not rise greatly even after several hours of infusion, unlike fentanyl.
Can clearance exceed hepatic blood flow?
Answer
Yes, because clearance is additive and extrahepatic routes exist. Propofol’s clearance of about 2.2 L·min⁻¹ exceeds liver blood flow, indicating extrahepatic metabolism which may reach 40%, with the kidneys responsible for up to 30%.
Does CSHT tell you when the patient will wake?
Answer
Not necessarily. During long, stimulating surgery, infusion rates will have been high, and the concentration at which waking occurs may be much less than half the concentration at the end of the infusion. Time to awakening may therefore substantially exceed the CSHT. This is why TCI pumps display a decrement time rather than a CSHT.
Define decrement time.
Answer
The time for plasma or effect-site concentration to fall by a specified percentage — 20%, 50%, 80%. CSHT is simply the 50% decrement time.
Why does a smaller propofol dose produce a higher peak effect-site concentration, and why is onset still slower?
Answer
They are two separate changes that happen to point in opposite directions.
Higher peak: the central compartment is smaller, so a given dose is diluted into less volume and the plasma concentration driving transfer to the brain is higher.
Slower onset: cardiac output is lower and circulation time longer, so that concentration takes longer to arrive, and blood–brain equilibration is slower.
Hence: give less, give it slowly, and wait before repeating. The error is topping up before the first dose has arrived.
Give one drug whose loading dose you would reduce and one whose maintenance rate you would reduce, and explain why they are different questions.
Answer
Loading dose = Vd × target concentration. It depends on volume alone. Reduce it for a hydrophilic drug whose Vd falls — digoxin, gentamicin.
Maintenance rate = clearance × target concentration. It depends on clearance alone. Reduce it for a drug whose clearance falls — morphine, or anything renally eliminated.
They are different questions because they are governed by different parameters. A patient in renal failure needs the same loading dose and a smaller maintenance rate.