Show the model answerAttempt it first — that is what makes it stick
First of three
Absorption
What earns the marksby ADME
| Work through ADME | Absorption, distribution, elimination — then pharmacodynamics |
|---|---|
| Say the direction | Which way each parameter moves, and why |
| Then the consequence | What it means for dosing |
| Change with ageing | Mechanism | Effect on absorption |
|---|---|---|
| ↑ gastric pH | Reduced parietal cell mass, atrophic gastritis | Altered ionisation of weak acids and bases; altered dissolution of some formulations |
| Delayed gastric emptying | Reduced motility | Later Tmax, lower Cmax — a slower, flatter curve |
| ↓ splanchnic blood flow | Reduced cardiac output and regional flow | Slower absorption |
| ↓ absorptive surface area and motility | Villous atrophy, reduced transit | Small effect on extent |
| ↓ active transport | Carrier-mediated uptake declines | Affects iron, calcium, some sugars; passive diffusion largely unaffected |
Read the question: The stem asks only about absorption, distribution and elimination. Writing a page on pharmacodynamics here earns no marks — it is set out below only because the same ground is examined directly in 2003 and 2015.
Read the question: Absorption is the least changed of the four. State that explicitly rather than inventing a large effect — the marks are in distribution, elimination and pharmacodynamics.
The headline: the rate of absorption slows, but the extent is largely unchanged for drugs absorbed by passive diffusion. Oral bioavailability by this route needs no routine adjustment.
Other routes. Intramuscular and subcutaneous absorption is erratic — reduced muscle mass and poorer peripheral perfusion — and injection is more painful; avoid the route. Transdermal absorption is variable with dermal thinning and reduced skin hydration.
Second of three
Distribution
Body composition. Total body water falls by roughly 10–15%, lean body mass falls, and fat rises as a proportion of body weight.
| Drug type | Vd | Consequence | Practical effect |
|---|---|---|---|
| Hydrophilic | ↓ | The same dose produces a higher initial plasma concentration | Reduce the loading dose — digoxin, gentamicin, neuromuscular blockers |
| Lipophilic | ↑ | Larger reservoir, slower terminal decline | Prolonged action and accumulation on repeated dosing — diazepam, thiopentone, fentanyl |
Protein binding. Albumin falls, particularly with intercurrent illness or malnutrition, raising the free fraction of acidic drugs — phenytoin, warfarin, diazepam, NSAIDs. α₁-acid glycoprotein is unchanged or rises as an acute-phase reactant, which if anything reduces the free fraction of basic drugs.
Third of three
Elimination
| Change | Magnitude | Which drugs it affects, and why |
|---|---|---|
| ↓ liver mass | 20–40% by the eighth decade | Fewer functioning hepatocytes, so less total enzyme capacity |
| ↓ hepatic blood flow | 35–40% | Rate-limiting for flow-limited (high extraction ratio) drugs — morphine, propranolol, lidocaine, propofol — whose clearance tracks delivery rather than enzyme activity, so clearance falls in proportion |
| ↓ enzyme activity | Variable | Rate-limiting for capacity-limited (low extraction ratio) drugs, whose clearance depends on intrinsic enzyme activity and free fraction rather than on flow |
| Phase I ↓ more than Phase II | — | Oxidation, reduction and hydrolysis decline; glucuronidation, sulphation and acetylation are relatively preserved. Hence prefer lorazepam, oxazepam or temazepam — conjugated directly — over diazepam, whose Phase I metabolism yields the long-acting active metabolite desmethyldiazepam |
| ↓ first-pass metabolism | — | Reduced hepatic extraction raises the oral bioavailability of high-extraction drugs, so the same oral dose produces a higher systemic concentration |
| Change | Magnitude | Consequence |
|---|---|---|
| ↓ GFR | ≈1% per year after the age of 40 | Reduced filtration of renally cleared drugs and their active metabolites |
| ↓ renal mass and glomerular number | 20–30% by the eighth decade | Fewer functioning nephrons; cortical loss exceeds medullary |
| ↓ renal blood flow | ≈10% per decade after 40 | Less delivery to the filtering and secreting apparatus |
| ↓ tubular secretion | — | Affects actively secreted drugs independently of the fall in filtration |
| ↓ concentrating ability | — | Reduced ability to handle a water or sodium load in either direction |
| Accumulation | — | Renally cleared drugs and active metabolites accumulate: morphine-6-glucuronide, desmethyldiazepam, digoxin, gentamicin, pancuronium |
Tying the three together
Why the effect is larger than any single change
For a lipophilic drug in an elderly patient, Vd rises and clearance falls — the half-life is prolonged by both terms at once, which is why the effect is so much larger than either change alone suggests. Time to steady state is prolonged in proportion, and context-sensitive half-time after an infusion is longer.
| Clinical consequence | Action |
|---|---|
| Higher initial concentration from a standard dose | Reduce induction and loading doses |
| Slower circulation time | Inject slowly; wait before repeating |
| Reduced clearance | Reduce maintenance and infusion rates, not just the bolus |
| Accumulation of lipophilic drugs and active metabolites | Avoid long-acting benzodiazepines; anticipate delayed emergence |
| Reduced first-pass extraction | Reduce oral doses of high extraction ratio drugs |
| Misleading serum creatinine | Estimate creatinine clearance before dosing renally cleared drugs |
Beyond this question
Pharmacodynamic changes
The general principle. The elderly are more sensitive to most anaesthetic drugs: a given plasma or effect-site concentration produces a greater effect. This is separate from, and additional to, the kinetic changes above — a higher concentration acting on a more sensitive target.
Central nervous system
- Neuronal density, brain mass, neurotransmitter concentrations and receptor density all fall.
- Sensitivity rises to opioids, benzodiazepines, propofol and the volatile agents. MAC falls by approximately 6% per decade after the age of 40.
- Propofol requirement falls for two reasons at once — a smaller central compartment and a more sensitive brain. Age is an explicit covariate in the Schnider and Eleveld models for exactly this reason.
- Greater risk of postoperative delirium and cognitive dysfunction. Mind the anticholinergic burden: atropine crosses the blood–brain barrier, glycopyrrolate does not.
| System | Change | Consequence |
|---|---|---|
| Baroreceptor reflex | ↓ sensitivity | Exaggerated hypotension on induction; less tachycardic compensation |
| β-adrenoceptors | ↓ responsiveness, reduced post-receptor signalling | Blunted response to β-agonists and to β-blockers |
| α-adrenoceptors | Relatively preserved | Phenylephrine or metaraminol is often more effective than ephedrine |
| Ventricular compliance | ↓, with increased arterial stiffness | More dependent on preload and atrial contraction; poorly tolerates vasodilatation or loss of sinus rhythm |
Respiratory and homeostatic reserve
Blunted ventilatory response to hypoxia and hypercapnia, so greater sensitivity to opioid-induced respiratory depression and to residual neuromuscular block. Impaired thermoregulation, volume regulation and renal concentrating ability leave less reserve to absorb any insult.
Sensitivity to warfarin is also increased at any given dose, independently of its kinetics.
If this came up in the viva
Viva points
Why does oral bioavailability of propranolol rise in the elderly when absorption from the gut is essentially unchanged?
Answer
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.
Which is affected more by ageing, Phase I or Phase II metabolism — and which benzodiazepine would you therefore choose?
Answer
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.
An 82-year-old has a serum creatinine of 90 µmol·L⁻¹. Is renal function normal?
Answer
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.
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.
A rocuronium block lasts longer in an 80-year-old. Is that pharmacokinetic or pharmacodynamic? Which relaxant would behave differently, and why?
Answer
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.
Ageing reduces the response to β-blockers as well as to β-agonists. Why does the same change affect both?
Answer
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.