If you read PS51 on medication safety, you will notice that it recommends the use of “Smart pumps”. Pharmacokinetic models are considered a fundamental part of modern anaesthetic practice, and you should understand their characteristics well.

*The following question is important: *

This graph shows the curves calculated for individual patients in a Midazolam pharmacokinetics study. You will note that one of the curves looks strange. I suspect there was a transcription error with one of the constants. Apart from this patient though, this is neither a best, nor a worst case graph.

• T/F The predictive accuracy of a pharmacokinetic model is ±10%

*The following concept is fundamental. You should be able to explain both what happens and why.*

You can see here the effect of haemorrhagic shock on effect site concentrations after a bolus dose of propofol. These graphs are based on pharmacokinetics from a pig study. You will note that pigs have different pharmacokinetics to humans. All the pigs were bled to a specific blood pressure, so the effect in a shocked patient might be less or more than this example.

Scroll down and look at the differences in the graphical representations of the control and shocked models. See if you can figure out why the curves are different.

• T/F Paradoxically the dose of propofol should be increased in haemorrhagic shock

*The next concept is something you should understand.*

Which of Schnider & Marsh has the larger central compartment? Now look at the difference between effect site and plasma concentrations with the Schnider and Marsh models.

• T/F The ratio of maximum plasma concentration to maximum effect site concentration is greater in models with a larger central volume of distribution

This is important because if you are using a model targeting plasma concentration, the initial bolus will be proportional to the size of the central compartment. Another issue to be aware of is that the central compartment size in the Schnider model is fixed. This means that all patients, regardless of size, would be given the same initial bolus if you used plasma concentration mode with the Schnider model.

*This concept is interesting but less important.*

Look at the difference between effect site and plasma concentrations with a model for vecuronium and for dexmedetomidine. Both have roughly the same central volume of distribution. Look at their times to peak effect. Try shortening the TTPE for dexmedetomidine and see what happens to the maximum plasma concentration.

• T/F The ratio of maximum plasma concentration to maximum effect site concentration is greater in drugs with a long time to peak effect

*The last question tests your understanding of how these models work.*

Take a look again at the time course of plasma concentration and effect site concentrations in the Schnider model for propofol. Take a look at some of the other drugs and see if it is the same.

• T/F Plasma concentration is equal to effect site concentration at ln(2) x the time to peak effect

*I have put the following in small print because it is not a pass/fail concept.*

When we look at the relationship between plasma concentration and effect, we notice that the effect lags the concentration in both onset and offset. We can correct for this by introducing a mathematical lag. The ‘effect’ site concentration is therefore a lag corrected plasma concentration rather than a real entity. If we could actually measure the concentration at the effect site, what would it be? The experiment is actually possible with microdialysis catheters. In this study, they found the actual tissue concentrations of cefazolin were about an order of magnitude less than the plasma concentrations.

It is not possible to simulate this using a standard mammillary model, as the effect site concentration in these models will always eventually approximate that of the central compartment.. How can you explain this discrepancy?