5 questions
Clearance
- What do you understand by the term “clearance”?
- Using midazolam as an example, the importance of clearance.
- Explain zero and first order kinetics by using examples6
- Discuss the pharmacokinetics of drugs administered via the rectal route4
- (a)Explain zero and first order kinetics by using examples.6 marks
- (b)Discuss the pharmacokinetics of drugs administered via the rectal route.4 marks
- How does the kidney excrete drugs?7
- How might chronic renal failure affect drug handling3
- (a)Describe how drugs are handled by normal kidneys8
- (b)List other routes of drug excretion with ONE example of drug relevant in anaesthesia practice for each routes2
2 questions
Half-life / CSHT
- Describe how 'context sensitive half time' of a drug differs from its 'half life'4
- Explain the properties of propofol that makes it suitable as a sedative agent6
- (a)Briefly explain the factors determining the therapeutic effects of propofol during induction of anaesthesia.6 marks
- (b)Differentiate between half-life and context-sensitive half-life of propofol.4 marks
3 questions
Volume of distribution
- Outline, with examples the physicochemical factors affecting drug distribution6
- Discuss the distribution of drugs across the blood brain barrier4
- Discuss the changes in the elderly that affect drug distribution including clinical implications examples.
- Describe using a graph on how target-controlled infusion (TCI) Propofol reaches a target concentration of 4mcg/ml
- Define volume of distribution
- Briefly explain the physicochemical factors that affect the distribution of drugs with - Low volume of distribution - High volume of distribution Provide examples for your explanation
- How does obesity influence the pharmacokinetics of the anaesthetic drugs?
3 questions
Bioavailability / extraction
- Define oral bioavailability and how would you measure it?1.5
- What factors influence oral bioavailability?8
- Give an example of a useful drug with an oral bioavailability of zero?0.5
- Define bioavailability and how it is measured3
- With regards to the oral route, describe the factors that determine the drug fraction reaching systemic circulation7
- Define bioavailability of a drug1
- How oral bioavailability is calculated2
- Discuss the factors that affect oral bioavailability7
6 questions
Hepatic handling
- What is drug biotransformation and what factors can affect it?
- Give drug examples in your answer.
Discuss with examples the importance of extrahepatic metabolism of drugs in relation anaesthesiology practice.
- Describe Phase I and Phase II reactions in drug metabolism.
- Provide examples with anaesthesia.
- How are drugs metabolized in the liver and what factors influence it?5
- Outline the effects of liver failure on the pharmacokinetics of drugs5
- Outline the role of the liver in the drug pharmacokinetics10
- A 58-year-old man with alcoholic liver cirrhosis is scheduled for emergency laparotomy. Preoperative blood tests show hypoalbuminaemia.
- (a)Define hepatic extraction ratio.1 mark
- (b)State the factors that determine hepatic extraction ratio.1 mark
- (c)Discuss drugs with high and low extraction ratio and the effects of liver disease on each group. Provide one (1) example of drug for each group.6 marks
- (d)State the clinical implications for drug dosing in this patient.2 marks
7 questions
Models, TCI, infusions
- What are the desirable pharmacokinetic and pharmacodynamic characteristics of a drug use in Total Intravenous Anaesthesia?
- Illustrate your answer with clinical examples appropriate
- Describe the mechanism of action of propofol2
- How is it eliminated?2
- Discuss its suitability for total intravenous anaesthesia)6
- Using three-compartmental model, explain the pharmacokinetics of propofol
- (a)following a single intravenous bolus.4 marks
- (b)in a target-controlled infusion (TCI).6 marks
- Outline the metabolism of opioids5
- Describe the suitability of Remifentanil in Total Intravenous Anaesthesia (TIVA)
- What are the advantages of total intravenous anaesthesia (TIVA)?3
- What is the ideal agent for TIVA and why?2
- Briefly describe the pharmacokinetic models used in a target-controlled infusion (TCI). variables are used in calculating the loading dose and maintenance dose in TCI?5
Propofol and sodium thiopentone: pharmacokinetics and central nervous system effects.
- Describe the factors that influence the speed at which inhalational anaesthetic agents steady state8
- Describe the effects of inhaled anaesthetic agents on the skeletal muscle2
4 questions
Ageing and special populations
- Explain the effects of old age on drug:
- (a)absorption
- (b)distribution
- (c)elimination
- Discuss briefly how ageing alters the pharmacodynamics and pharmacokinetic propertied anaesthetic drugs.
- Give examples where appropriate.
- How does pregnancy at term influence the pharmacokinetics of anaesthetic drugs?
- What factors influence the rate of transfer of drugs across the placenta?4
- How do these factors explain the adverse effects of pethidine and local anaesthetics when administered during labour?2
- Propofol is a drug commonly used in the administration of total intravenous anaesthesia (TIVA)
- (a)Describe the desirable pharmacokinetic features of propofol that make it suitable for TIVA.6 marks
- (b)Explain the pharmacological considerations that should be taken when administering TIVA in an elderly patient.4 marks
Single best answer
9 SBAs on pharmacokinetics
Viva
36 viva questions
- Core
Why is midazolam water-soluble in the ampoule but lipid-soluble in the patient?
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The ampoule is buffered to about pH 3.5, at which the imidazole ring is open and the molecule ionised and water-soluble. At pH 7.4 the ring closes and the drug becomes lipophilic.
- Applied
Why do local anaesthetics fail in infected tissue?
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Abscess pH is low, so a weak base of pKa around 8 is almost entirely ionised and very little unionised drug is available to cross the axolemma. Increased local perfusion also removes drug faster.
- Core
Why does glycopyrrolate not cause central anticholinergic effects when atropine does?
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Glycopyrrolate is a quaternary ammonium compound, permanently charged regardless of pH, therefore hydrophilic and unable to cross the blood–brain barrier. Atropine is a tertiary amine and does cross.
- Applied
Can clearance exceed hepatic blood flow?
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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%.
- Applied
Can clearance exceed cardiac output?
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Yes, if elimination occurs within blood or tissue rather than requiring delivery to an organ — remifentanil and atracurium are the standing examples.
- Core
What is the clearance of a drug removed entirely by the kidney in one pass?
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Renal plasma flow, approximately 650 mL·min⁻¹. Para-aminohippuric acid is used to measure it for exactly this reason.
- Applied
Why does cirrhosis affect some drugs and not others?
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It acts by two mechanisms simultaneously. Reduced functional hepatocyte mass and enzyme activity impairs clearance of low-ER drugs. Portosystemic shunting bypasses the liver and dramatically raises the oral bioavailability of high-ER drugs. Hypoalbuminaemia additionally raises fu, further increasing clearance of binding-sensitive low-ER drugs.
- Applied
Why is oral propranolol dosed so differently from intravenous?
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High ER means most of an oral dose is destroyed on first pass, and small individual differences in liver blood flow produce large differences in the fraction surviving. Hence roughly 80 mg per day intravenously against 240 mg per day orally. And why this widens in the elderly
- Applied
Why can a drug have a bioavailability that rises in liver disease?
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Because reduced first-pass extraction allows more of the oral dose through — the effect is largest for high-ER drugs, where first pass normally destroys most of the dose.
- Core
Define Km and give its units.
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The substrate concentration at which the reaction proceeds at half its maximum velocity; units of concentration. A low Km indicates high affinity.
- Core
Why does ethanol follow zero-order kinetics at ordinary drinking concentrations?
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Alcohol dehydrogenase has a very low Km relative to the blood concentrations achieved, so the enzyme is saturated from the first drink. At very low blood concentrations it does revert to first-order — but at levels so low that no effect is detectable.
- Applied
Why is half-life a poor descriptor of saturable (Michaelis–Menten) elimination?
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Because t½ = 0.693 Vd/Cl requires clearance to be constant. Under saturation, Cl = Vmax/(Km + C) varies with concentration, so the half-life changes throughout elimination and with the dose given.
- Applied
Give a non-metabolic example of saturable behaviour.
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Carrier-mediated transport — active tubular secretion, where the acid and base pumps are capacity-limited and competitively inhibited, and biliary canalicular transport.
- Core
Why is propofol suitable for TIVA?
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Its CSHT does not rise greatly even after several hours of infusion, unlike fentanyl.
- Applied
Does CSHT tell you when the patient will wake?
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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.
- Core
Define decrement time.
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The time for plasma or effect-site concentration to fall by a specified percentage — 20%, 50%, 80%. CSHT is simply the 50% decrement time.
- Applied
Why does oral bioavailability of propranolol rise in the elderly when absorption from the gut is essentially unchanged?
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Bioavailability is the fraction absorbed multiplied by the fraction surviving first pass, so F = fabs × (1 − ER). Ageing leaves the first term alone and changes the second.
Reduced liver mass and hepatic blood flow lower hepatic extraction. Propranolol has a high extraction ratio, so normally only a small fraction survives the first pass — and when the surviving fraction is small, a modest fall in extraction is a large proportional rise in what reaches the systemic circulation. Reduce the oral dose.
- Core
Which is affected more by ageing, Phase I or Phase II metabolism — and which benzodiazepine would you therefore choose?
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Phase I. Oxidation, reduction and hydrolysis decline while conjugation is relatively preserved. Choose lorazepam, oxazepam or temazepam, which are conjugated directly and have no active metabolite. Diazepam is oxidised by Phase I to desmethyldiazepam, which is active, long-acting and accumulates.
- Applied
An 82-year-old has a serum creatinine of 90 µmol·L⁻¹. Is renal function normal?
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The creatinine is normal; renal function may well not be. Creatinine production is proportional to muscle mass, which falls with age, so a value near the top of the reference range in a small, elderly patient is compatible with a substantially reduced GFR. Estimate the clearance — an equation that takes age and weight into account — before dosing anything renally cleared.
- Applied
Why does a smaller propofol dose produce a higher peak effect-site concentration, and why is onset still slower?
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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.
- Applied
Give one drug whose loading dose you would reduce and one whose maintenance rate you would reduce, and explain why they are different questions.
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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.
- Applied
A rocuronium block lasts longer in an 80-year-old. Is that pharmacokinetic or pharmacodynamic? Which relaxant would behave differently, and why?
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Pharmacokinetic. Sensitivity at the neuromuscular junction is essentially unchanged by age; the prolongation comes from reduced hepatic and renal clearance. Atracurium and cisatracurium behave differently because Hofmann elimination is organ-independent, so their duration changes little.
- Stretch
Ageing reduces the response to β-blockers as well as to β-agonists. Why does the same change affect both?
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Because the change is in the receptor–effector pathway, not in the drug. Reduced receptor responsiveness and impaired post-receptor coupling mean less signal is produced per unit of stimulation. An agonist therefore generates less effect, and an antagonist has less ongoing β-mediated tone to remove. Both depend on the gain of the same pathway, and the gain has fallen.
Why is first-order elimination called linear kinetics when its ordinary plot is curved?
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Because pharmacokinetic exposure changes proportionally with dose and clearance remains constant. The concentration–time relationship is exponential on linear axes but linear after logarithmic transformation.
Does a zero-order drug remain zero order until all drug is gone?
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No. Saturable elimination usually becomes first order once concentration falls sufficiently below Km.
Which rectal vein enters the portal system?
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The superior rectal vein, via the inferior mesenteric vein.
Why is rectal absorption unpredictable?
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Small surface area, limited dissolution fluid, faeces, contact time/expulsion, formulation, position, perfusion, mucosal condition and mixed portal/systemic drainage.
Why does a patient wake rapidly after one thiopentone bolus despite slow metabolism?
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Redistribution lowers brain concentration before most drug has been eliminated.
Why is thiopentone recovery prolonged after an infusion?
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Peripheral compartments fill, drug later returns to plasma, clearance is low and metabolism becomes capacity-limited at high exposure.
How does acidaemia alter thiopentone effect?
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As a weak acid, thiopentone becomes more unionised as pH falls, increasing lipid solubility and CNS penetration; critical illness may simultaneously increase its free fraction.
Why can CPP fall even though the agent reduces ICP?
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CPP equals MAP minus ICP. If MAP falls more than ICP, CPP decreases.
Which drug is antiemetic?
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Propofol; thiopentone has no useful intrinsic antiemetic action.
Propofol has a long terminal half-life. Why does the patient wake up quickly?
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Because waking is determined by redistribution out of the central compartment and by a high clearance, not by the terminal phase. The long terminal half-life reflects a small amount of drug returning slowly from poorly perfused tissue — far too little to maintain anaesthesia. The concentration at the effect site has already fallen below the waking threshold long before that phase dominates.
Why is propofol clearance greater than liver blood flow?
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Because metabolism is not confined to the liver. There is significant extra-hepatic metabolism, principally in the lung. A drug cleared solely by the liver cannot have a clearance exceeding hepatic blood flow, so a measured clearance above it is itself the evidence for an extra-hepatic route.
Your patient is in septic shock. How does that change the induction dose?
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Reduce it substantially, and wait longer. A low cardiac output reduces the initial volume of distribution, so the same dose gives a higher peak concentration; hypoalbuminaemia raises the free fraction; and reduced cerebral autoregulatory reserve makes the cardiovascular depression less tolerable. Arrival is also slower, so the temptation is to re-dose before the first dose has acted.
Why does remifentanil have an almost flat context-sensitive half-time?
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Because it is hydrolysed by non-specific plasma and tissue esterases, which act on drug wherever it is rather than only on drug delivered to an organ. Clearance is therefore very high and independent of hepatic and renal function, and peripheral accumulation never becomes the rate-limiting step when the infusion stops.