2011B02 What is
meant by the term “two compartment model” in pharmacokinetics?
Use propofol as an example in explanation.
List:
· Intro
· Two compartments: features
· Two compartments: sources of error
· Alternative models
Intro:
Aim of pharmacokinetic model: to predict drug concentration during induction, maintenance and offset of anaesthesia
Two compartment model: features
|
Diagramme |
|
|
Graph and equation |
· Bi-exponential decay curve: C = Ae-at + Be-bt |
|
Description |
· Propofol injected into V1 · Effect correlates with [propofol] in V1 · Fast distribution phase (distribution+++ metabolism ++) · Slower terminal elimination phase (metabolism++ offset by redistribution+) |
|
Derivation |
· Experiment in healthy volunteers · Propofol infusion at various rate, various duration (1min to 8h) · Serial blood sampling · Plot Cp vs time · Non-linear regression analysis -> equations, rate constants, compartment volumes |
|
Suitability of propofol |
· Reasonably modelled by two compartments (VDC 0.3-0.6L/kg, VDSS 4L/kg) · Rapid but biphasic distribution (t1/2α fast 2 mins, t1/2α slow 50 mins) · Slow terminal elimination (t1/2β 5-12 hours) |
Two compartment model: sources of error:
|
Inaccurate modelling |
· Body has billions of discrete cell compartments, not 1 or 2 or 3 · Variation in compartment volumes (e.g. shock), clearance rate (e.g. organ failure) · Inaccurate for induction kinetics (cardiac output and central blood volume more important) · Small sample size of experiments |
|
Inaccurate assumptions |
· No delay between reaching threshold Cp and onset of effect (e.g. lag described by ke0) · [Drug] in V1 correlates immediately with effect (e.g. effect site may be in periphery e.g. rocuronium) · Elimination always from V1 (e.g. remifentanil metabolized in periphery) · Elimination not always first order (e.g. thiopentone zero order in physiological range) |
|
Consequences of error |
· Overdose -> CVS toxicity · Underdose -> awareness |
Alternative models:
|
Single compartment |
· Not a good representation · Whole-body equilibration not immediate · Predicted loading dose based on VDSS is fatal |
|
Three compartment |
· Better model for most drugs · E.g. propofol: t1/2α fast, t1/2α slow and t1/2β |
|
Four or more compartments |
· No significant advantage over three |