What you should already have
About 65 minutes
Plus the time it takes to redraw this lesson’s figures from memory, which is the fastest way to find out what you have not understood.
Where this shows up
The kinetics in the previous lesson assume an average adult, and almost nobody on a theatre list is one. This lesson takes each ADME step and asks what pregnancy, childhood, age, obesity and critical illness do to it — so that a dose adjustment is derived from a mechanism rather than recalled from a table.
Learning outcomes
By the end of this lesson you should be able to:
- Predict how a change in body composition, protein binding, cardiac output or organ function alters each ADME step.
- Describe the kinetic changes of pregnancy at term, and the two distinct mechanisms by which drugs reach the fetus.
- Describe the kinetic changes of childhood, and say which of them are not simply a matter of size.
- Describe the kinetic changes of ageing, separating what ageing itself does from what its comorbidities do.
- Describe the effect of obesity, and choose between total, lean and adjusted body weight for a given drug.
- Describe the kinetic changes of critical illness, including altered protein binding and augmented renal clearance.
- Perform the standard pharmacokinetic calculations, defining every symbol and stating its units.
Together these settle 2 syllabus objectives: Altered pharmacokinetics in pregnancy, children, ageing, obesity and critical illness and The standard pharmacokinetic calculations. Tick them on the Pharmacology objective list once you can do all of the above without notes.
Part VII
Special populations
These are the most frequently examined applications of pharmacokinetics and among the worst answered. The recurring failure identified in the examiner critique is structural rather than factual: candidates write generic ADME without relating it to the population, or describe the population without relating it to kinetics. Answer within the ADME framework, but make every point a statement about that population, and finish each with its clinical implication.
Everything on one page
Master comparison across populations
| Variable | Pregnancy (term) | Term neonate | Child 1–8 y | Elderly | Obesity | Critical illness |
|---|---|---|---|---|---|---|
| Absorption | ||||||
| Gastric emptying | ↓ (especially in labour) → ↑ absorption in stomach and upper GI tract | ↓ and irregular | Approaches adult | ↔ in the absence of disease | Often ↑ emptying | ↓↓ — gastroparesis common; enteral absorption unreliable |
| Intramuscular / subcutaneous | ↑ uptake — high cardiac output and vasodilatation | Variable — low muscle mass | Reliable | ↓ and erratic — reduced muscle mass | Unreliable — needle may not reach muscle | Unreliable — poor peripheral perfusion |
| Distribution | ||||||
| Total body water | ↑↑ (plasma volume ↑ 40–50%) | ↑↑ 75–80% body weight (preterm ≈85%) | ↑ ≈65% | ↓ | ↑ absolute, ↓ as a fraction | ↑↑ — capillary leak, fluid resuscitation, third-space loss |
| Vd hydrophilic drugs | ↑ | ↑↑ — larger mg·kg⁻¹ loading dose required | ↑ | ↓ — smaller doses required | ↑ modestly | ↑↑ — under-dosing is the classic error |
| Vd lipophilic drugs | ↑ | ↓ — low fat mass | ↑ (fat peaks ≈1 y) | ↑ — prolonged action, accumulation | ↑↑ | Variable |
| Albumin | ↓ from first trimester, nadir in third | ↓ and fetal albumin binds less avidly | Adult by ≈1 y | ↓ | ↔ or ↓ | ↓↓ — free fraction of acidic drugs ↑ |
| α₁-acid glycoprotein | ↓ | ↓↓ | Adult by ≈1 y | ↔ or ↑ | ↔ | ↑ — acute-phase reactant; free fraction of basic drugs ↓ |
| Cardiac output | ↑ 30–50%, from 4 to 6 L·min⁻¹ | ↑ per kg | ↑ per kg | ↓ — slower circulation time, slower onset | ↑ absolute | ↑ in hyperdynamic sepsis; ↓ in shock |
| Metabolism | ||||||
| Hepatic blood flow | ↑ | ↓ — ductus venosus shunting in the first days | ↑ per kg | ↓ — with reduced liver size | ↑ absolute; fatty infiltration | ↓ in shock and with vasopressors |
| Phase I (CYP) | ↑ CYP3A4 from end of first trimester | ↓↓ immature | ↑ may exceed adult rates | ↓↓ — affected more than Phase II | Variable; may be ↓ | ↓ — cytokine-mediated suppression |
| Phase II (conjugation) | ↑ | ↓ — glucuronidation matures by 3–6 months | ↑ | Relatively preserved | ↔ or ↑ | Relatively preserved |
| Excretion | ||||||
| GFR | ↑↑ — enhanced excretion of renally cleared drugs | ↓↓ ≈10 mL·min⁻¹·1.73 m⁻² at birth | Adult values from ≈1 y | ↓ ≈1% per year after 40 | ↑ early; glomerulopathy later | Bidirectional — augmented renal clearance or acute kidney injury |
| Net effect | ||||||
| Dominant practical risk | Faster onset and larger unbound fraction; drug transfer to fetus | Accumulation — half-lives 2–3× longer | Under-dosing on a mg·kg⁻¹ basis | Accumulation and prolonged effect; polypharmacy | Choosing the wrong weight scalar | Unpredictable in both directions — monitor rather than predict |
Two patients, one dose
Pregnancy
| Variable | First trimester | Second trimester | Third trimester / term | Pharmacokinetic consequence |
|---|---|---|---|---|
| Cardiac output | ↑ — about 75% of the total rise achieved | Continues to rise | ↑ 30–50% overall (4 → 6 L·min⁻¹); peaks ≈32 weeks | Faster delivery to effect site; faster onset. Increased uptake of drugs given subcutaneously, intramuscularly or neuraxially |
| Plasma volume, total body water | ↑ from 6 weeks | ↑↑ | Plasma volume ↑ 40–50% | ↑ Vd, particularly for hydrophilic drugs; dilutional fall in concentration for a given dose |
| Albumin | Begins to fall | Falling | Nadir | ↑ free fraction of acidic drugs (thiopentone, phenytoin, warfarin) |
| α₁-acid glycoprotein | Begins to fall | Falling | Reduced | ↑ free fraction of basic drugs (local anaesthetics, opioids) |
| CYP3A4 activity | ↑ by end of first trimester | Remains elevated | Remains elevated | ↑ metabolism of drugs highly dependent on hepatic metabolism |
| Hepatic blood flow | ↑ | ↑ | ↑ | ↑ clearance of high extraction ratio drugs |
| GFR and renal blood flow | ↑ from 6 weeks | ↑↑ | Peaks ≈32 weeks | ↑ excretion of renally cleared drugs — may cause therapeutic failure |
| Gastric emptying | ↔ | ↔ | ↓, markedly so in labour and with opioids | Increased absorption in stomach and upper GI tract owing to longer contact time; also aspiration risk |
| Minute ventilation | ↑ | ↑ | ↑ 50%, with ↓ FRC | Faster inhalational induction; MAC reduced ≈30% |
| Progesterone | ↑ | ↑ | ↑ | ↑ sensitivity to local anaesthetics; reduced anaesthetic requirement |
Placental transfer — state how each factor acts
| Fick variable | Determined by | How it influences transfer |
|---|---|---|
| Concentration gradient | Maternal dose, rate of injection, maternal clearance, uteroplacental blood flow | The driving force. A rapid intravenous bolus creates a steep transient gradient and maximises transfer |
| Surface area (A) | Placental size and health | Reduced in placental insufficiency, pre-eclampsia and infarction |
| Membrane thickness (d) | Placental maturity | Thins with advancing gestation, so transfer increases towards term |
| Diffusion constant — molecular weight | Size of the molecule | <500 Da crosses readily; >1000 Da poorly — heparin and neuromuscular blockers do not cross |
| Diffusion constant — lipid solubility | Physicochemistry | High lipid solubility permits rapid transfer — the mechanism for pethidine |
| Diffusion constant — ionisation | pKa and fetal pH | Only the unionised fraction crosses — the mechanism for ion trapping |
| Diffusion constant — protein binding | Albumin and α₁-acid glycoprotein on each side | Only free drug crosses; equilibrium is of free drug only |
Not small adults
Paediatrics
| Variable | Preterm | Term neonate 0–28 days | Infant 1–12 months | Young child 1–5 years | Child 6–12 years | Adolescent |
|---|---|---|---|---|---|---|
| Total body water (% weight) | ≈85% | 75–80% | ≈70% | ≈65% | ≈62% | ≈60% (adult) |
| Extracellular fluid (% weight) | ≈50% | ≈45% | ≈30% | ≈25% | ≈22% | ≈20% (adult) |
| Body fat | Very low | ≈15% | Peaks ≈25% at 1 y | Falling | Adult proportion | Adult; sex differences emerge |
| Vd water-soluble drugs | ↑↑↑ | ↑↑ | ↑ | Slightly ↑ | ≈ adult | Adult |
| Plasma proteins | ↓↓; fetal albumin binds less avidly | ↓; competition from bilirubin and free fatty acids | Rising | Adult levels from ≈1 year | Adult | Adult |
| Phase I (CYP) | Very immature | Immature | Rising rapidly over the first 6 months | May exceed adult rates | Declining towards adult | Adult |
| Phase II — glucuronidation | Very immature | Immature | Mature by 3–6 months | Adult or above | Adult | Adult |
| Acetylation | Absent | Reduced in the first month | Maturing | Adult | Adult | Adult |
| GFR | Very low; catches up with term peers by ≈3 y | ≈10 mL·min⁻¹·1.73 m⁻² at birth; 20–30 by 2 weeks | Rising; adult values by ≈1 year | Adult | Adult | Adult |
| Blood–brain barrier | Immature — ↑ CNS penetration | Immature | Maturing | Mature | Mature | Mature |
| Elimination half-life | ↑↑↑ | 2–3× adult for phenytoin, barbiturates, analgesics, cardiac glycosides | Falling towards adult | May be shorter than adult | ≈ adult | Adult |
A useful quantitative marker of hepatic maturation: microsomal protein content of the liver rises from approximately 26 mg·g⁻¹ in the neonate to a maximum of about 40 mg·g⁻¹ in a 30-year-old adult.
For preterm infants, renal maturation is slower still. For a child born at 26 weeks’ gestation, absolute GFR is approximately 18%, 63%, 80%, 92% and 96% of that of a child born at 40 weeks, measured at 1 month, 6 months, 1 year, 3 years and 12 years respectively — so GFR catches up with term peers at around three years of age. Reduced doses of renally cleared drugs should be considered below three years in the former preterm infant.
The paediatric propofol models — Paedfusor and Kataria — are covered in lesson 2. The essential number is Paedfusor’s central compartment volume of 458 mL·kg⁻¹, roughly double the adult Marsh value of 228 mL·kg⁻¹, which quantifies why children require larger weight-adjusted induction doses.
Ageing, not comorbidity
The elderly
| Change with ageing | Kinetic consequence | Clinical implication |
|---|---|---|
| Oral absorption little changed in the absence of disease | — | No routine adjustment for the oral route |
| Reduced muscle mass | Erratic intramuscular absorption | Avoid the intramuscular route; injection is also painful |
| ↓ total body water, ↑ fat fraction | ↓ Vd of hydrophilic drugs; ↑ Vd of lipophilic drugs | Smaller doses of water-soluble drugs; prolonged action and accumulation of lipid-soluble drugs on repeated dosing |
| ↓ albumin | ↑ free fraction of acidic drugs | Greater effect from the same total dose |
| ↓ liver size and hepatic blood flow | ↓ clearance; ↑ bioavailability of high extraction ratio drugs owing to reduced first pass | Reduce maintenance infusion rates and oral doses of high-ER drugs |
| Phase I affected more than Phase II | Oxidative metabolism reduced; conjugation relatively preserved | Prefer lorazepam or oxazepam over diazepam |
| ↓ GFR, ≈1% per year after age 40 | ↓ renal clearance and accumulation of active metabolites | Serum creatinine may be normal despite halved GFR because of low muscle mass — estimate creatinine clearance |
| ↓ cardiac output, slower circulation time | Slower delivery to the effect site | Slower onset — titrate slowly and wait before repeating a dose |
| ↑ t½ and ↑ time to steady state | Longer washout after infusions | Stop infusions earlier; anticipate delayed emergence |
| Polypharmacy | — | Substantially increased risk of interactions |
| Neuraxial changes | Reduced blood flow in the subarachnoid space; smaller CSF volume | Greater spread and effect of intrathecal local anaesthetic |
Which weight?
Obesity
| Change | Consequence |
|---|---|
| ↑ absolute fat mass and ↑ absolute lean mass (lean mass rises by roughly 20–40% of excess weight) | ↑ Vd for lipophilic drugs — thiopentone, benzodiazepines, propofol — giving a larger loading dose requirement and prolonged offset after repeated dosing. Vd for hydrophilic drugs rises much less |
| ↑ cardiac output and blood volume in absolute terms | Larger central compartment; increased organ blood flow |
| Hepatic steatosis; Phase I may be reduced, Phase II normal or increased | Variable and unpredictable clearance |
| ↑ GFR and renal blood flow early; glomerulopathy later | May increase clearance of renally excreted drugs early in the disease |
| ↑ α₁-acid glycoprotein; ↑ free fatty acids | Altered binding of basic drugs |
Where prediction fails
Critical illness, hepatic failure and renal failure
| Pathophysiology | Kinetic effect | Consequence |
|---|---|---|
| Capillary leak, aggressive fluid resuscitation, third-space losses | ↑↑ Vd of hydrophilic drugs, whose volume approximates extracellular fluid — β-lactams, aminoglycosides, neuromuscular blockers | Under-dosing is the classical error. Larger loading doses may be required |
| Hypoalbuminaemia from increased capillary permeability and reduced synthesis | ↑ free fraction of highly bound acidic drugs; ↑ Vd and ↑ clearance of that free drug | Total drug concentrations mislead; free levels may be adequate when total levels appear low |
| ↑ α₁-acid glycoprotein as an acute-phase reactant | ↓ free fraction of basic drugs | Reduced effect of some local anaesthetics and opioids at a given total concentration |
| Augmented renal clearance — increased cardiac output with reduced systemic vascular resistance | ↑↑ renal clearance | Subtherapeutic concentrations of renally cleared drugs; classically antibiotic failure in young trauma and sepsis patients |
| Acute kidney injury | ↓↓ renal clearance; accumulation of active metabolites | Toxicity — morphine-6-glucuronide, norpethidine, midazolam glucuronide |
| Shock, vasopressors, raised intra-abdominal pressure | ↓ hepatic blood flow → ↓ clearance of high extraction ratio drugs | Accumulation of propofol, lignocaine, morphine, midazolam |
| Cytokine-mediated suppression of cytochrome P450 | ↓ Phase I metabolism | Reduced clearance of low extraction ratio drugs |
| Gastroparesis and splanchnic hypoperfusion | Unreliable enteral absorption | Prefer the intravenous route |
| Renal replacement therapy | Clearance depends on modality, filter, flow rates, and on the drug's Vd and protein binding | Drugs with a large Vd are poorly removed however efficient the circuit |
| Extracorporeal membrane oxygenation | Sequestration in the circuit, greatest for lipophilic and highly protein-bound drugs; ↑ circuit volume | Propofol, fentanyl and midazolam are substantially sequestered; doses often need to be increased |
Hepatic and renal failure — summary logic
Two mechanisms at once
↓ enzyme activity → ↓ clearance of low ER drugs. Portosystemic shunting → ↓ first pass → ↑ oral bioavailability of high ER drugs. ↓ albumin → ↑ free fraction → ↑ Vd; total-drug monitoring misleads. Phase I lost before Phase II → prefer lorazepam, oxazepam, morphine. Ascites and oedema → ↑ Vd of hydrophilic drugs. t½ prolonged from both directions — ↑ Vd and ↓ Cl.
Parent drug and metabolite
↓ clearance of renally excreted drugs and of active metabolites. Adjust when a drug is >50% renally cleared and function is halved. Uraemia displaces acidic drugs from albumin → ↑ free fraction. Altered blood–brain barrier → ↑ CNS sensitivity to opioids and sedatives. Fluid overload → ↑ Vd of hydrophilic drugs. Metabolic acidosis alters ionisation and therefore distribution. Prefer atracurium and remifentanil.
Part VIII
Applied
Numerical application of everything above. A formula that can be quoted but not applied is not yet understood, so work through these with a pen rather than reading them.
Arithmetic you may be asked to do
Worked calculations
1Volume of distributionVd = Dose ÷ C₀
| Vd | = | 500 mg ÷ 12.5 mg·L⁻¹ | check that the units cancel to litres |
| Vd | = | 40 L (0.57 L·kg⁻¹) |
Interpret it. 40 L is close to total body water (≈42 L in a 70 kg adult), so Drug X distributes through total body water without substantial tissue sequestration — compare ethanol and urea.
2Rate constant and time constantk = 0.693 ÷ t½ ; τ = 1 ÷ k
| k | = | 0.693 ÷ 3 h | |
| k | = | 0.231 h⁻¹ | 23.1% of the drug present is eliminated each hour |
| τ | = | 1 ÷ 0.231 | |
| τ | = | 4.33 h | check: 0.693 × 4.33 = 3.0 h ✓ — the time constant is always the longer |
3ClearanceCl = 0.693 Vd ÷ t½ = k × Vd
| Cl | = | 0.693 × 40 L ÷ 3 h | |
| Cl | = | 9.24 L·h⁻¹ = 154 mL·min⁻¹ | cross-check: k × Vd = 0.231 × 40 = 9.24 ✓ |
Interpret it. 154 mL·min⁻¹ is close to GFR and far below hepatic blood flow, consistent with a low extraction ratio drug or predominantly renal elimination.
4Area under the curveAUC = Dose ÷ Cl
| AUC | = | 500 mg ÷ 9.24 L·h⁻¹ | |
| AUC | = | 54.1 mg·h·L⁻¹ | note the units — concentration × time |
Run the other way (Cl = Dose ÷ AUC), this is how clearance is measured in practice, using the trapezoid rule on real sampling data.
5Loading doseLD = Vd × Ctarget
| LD | = | 40 L × 4 mg·L⁻¹ | |
| LD | = | 160 mg |
Note what does not appear: clearance. If this patient developed renal failure, the loading dose would be unchanged. Only the maintenance rate changes.
6Maintenance rate, and the equivalent oral doserate = Cl × Css ; oral = rate ÷ F
| Maintenance rate | = | 9.24 L·h⁻¹ × 4 mg·L⁻¹ | |
| = | 36.96 ≈ 37 mg·h⁻¹ intravenously | = 296 mg per 8 hours | |
| oral dose per 8 h | = | 296 mg ÷ 0.40 | correct for bioavailability |
| = | 740 mg eight-hourly | the propranolol-style intravenous : oral disparity |
7Time to steady state, and time to fall from 20 to 5 mg·L⁻¹t = ln(C₀ ÷ C) ÷ k
Time to steady state = 4–5 half-lives = 12–15 hours, independent of the infusion rate.
Fall from 20 to 5 mg·L⁻¹ is a fall by a factor of four, i.e. two halvings:
| t | = | ln(C₀ ÷ C) ÷ k | rearranged from C = C₀e⁻ᵏᵗ |
| = | ln 4 ÷ 0.231 = 1.386 ÷ 0.231 | ||
| t | = | 6.0 hours | check: 2 half-lives × 3 h = 6 h ✓ |
8Extraction ratio, hepatic clearance and maximum oral bioavailabilityER = (Ca − Cv) ÷ Ca
A different drug has a hepatic inflow concentration of 10 mg·L⁻¹ and hepatic venous outflow of 2 mg·L⁻¹, with hepatic blood flow 1500 mL·min⁻¹.
| ER | = | (10 − 2) ÷ 10 | |
| ER | = | 0.8 | > 0.7 → high extraction, flow-limited |
| ClH | = | 1500 × 0.8 | |
| ClH | = | 1200 mL·min⁻¹ | |
| maximum oral F | = | 1 − 0.8 | assuming complete absorption and no gut-wall metabolism |
| F | = | 0.2 (20%) | so the oral dose must be about five times the intravenous dose |
Now predict. If cardiac output halves and hepatic blood flow falls to 750 mL·min⁻¹, clearance falls to approximately 600 mL·min⁻¹ — halved. Enzyme induction would barely change it. Verify this against Figure 5 in lesson 1.
9Michaelis–Menten — the phenytoin dose incrementCss = KmR ÷ (Vmax − R)
A patient has Vmax = 400 mg·day⁻¹ and Km = 6 mg·L⁻¹, taking 300 mg·day⁻¹. The dose is increased by 10%, to 330 mg·day⁻¹.
| Css at 300 mg/day | = | (6 × 300) ÷ (400 − 300) = 1800 ÷ 100 | |
| = | 18.0 mg·L⁻¹ | upper end of a typical 10–20 mg·L⁻¹ range | |
| Css at 330 mg/day | = | (6 × 330) ÷ (400 − 330) = 1980 ÷ 70 | |
| = | 28.3 mg·L⁻¹ | frankly toxic |
A 10% dose increase produced a 57% rise in concentration. Under linear kinetics it would have produced 10%. Compute the clearance at each concentration to see why:
| Cl at 18 mg·L⁻¹ | = | Vmax ÷ (Km + C) = 400 ÷ 24 | = 16.7 L·day⁻¹ |
| Cl at 28.3 mg·L⁻¹ | = | 400 ÷ 34.3 | = 11.7 L·day⁻¹ — clearance has fallen by 30% |
The answer to “why does this happen”. The drug is not merely accumulating; the body’s ability to remove it is falling as it accumulates. That positive feedback is what makes saturable kinetics dangerous, and why phenytoin requires small dose increments with therapeutic drug monitoring.
10Time constant — preoxygenation in a normal and an obese patientτ = FRC ÷ V̇A
| Normal: τ | = | FRC ÷ V̇A = 2.5 L ÷ 4.2 L·min⁻¹ | |
| = | 0.60 min → 3τ = 1.8 min for 95% denitrogenation | ||
| Obese (FRC 1.5 L): τ | = | 1.5 ÷ 4.2 | |
| = | 0.36 min → 3τ = 1.1 min |
The apparent paradox worth explaining in a viva. The obese patient denitrogenates faster — a smaller FRC is washed out more quickly. But that same small FRC is a smaller oxygen store, so desaturation on apnoea is far more rapid. Rapid preoxygenation and rapid desaturation are two consequences of the same reduced FRC.
11Creatinine clearanceCockcroft equation
A 70-year-old man, 70 kg, serum creatinine 100 µmol·L⁻¹:
| CrCl | = | (140 − 70) × 70 ÷ (0.814 × 100) | |
| = | 4900 ÷ 81.4 | ||
| CrCl | = | ≈ 60 mL·min⁻¹ | multiply by 0.85 for females |
The clinical point. This patient’s serum creatinine is entirely normal, yet clearance is roughly half that of a young adult. Low muscle mass produces less creatinine, so serum creatinine underestimates renal impairment in the elderly.