BT_GS 1.12 Effect Site Modelling

BT_GS 1.12

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?

Context Sensitive Half Time

BT_GS 1.12 Explain and describe the clinical application of concepts related to intravenous and infusion kinetics including: Concept of context sensitive half time

Context sensitive half time (CSHT) is a very important concept, and one which you should be prepared to discuss at length. This post discusses where these numbers come from.

All the textbooks show the same graph for CSHT of anaesthetic drugs. The graph comes from a paper by Hughes et al in 1992. You might be surprised to know that this graph is not of actual patient data, but the results of a simulation. The links in this post will allow you to reproduce these results, and also to see what happens if you use different pharmacokinetic models, or extend the time period.

This is the CSHT graph for midazolam using the data from Hughes’ paper. Click on the button labelled t75%. This will show you the context sensitive time to fall to 1/4 of the original concentration.  t87.5% shows the time to fall to 1/8 of the original concentration and t93.5% the time to fall to 1/16. How do these times compare to the half time? How do they compare to the terminal elimination half life? (You can see it here).

• T/F The time to fall to 1/4 of the original concentration is equal to twice the CSHT

Look at the graph for fentanyl. Now change the timescale of the graph from 8 hours to 16 or 24 hours and see what happens.

• T/F The CSHT for fentanyl continues to increase indefinitely with length of infusion.

Have a think and see if you can answer this question:

• T/F Drugs with a very variable CSHT are inappropriate to administer as a bolus.

The minimum standard for a pass would be to know and be able to discuss the CSHT graphs which are in the textbooks. The following is for more advanced understanding.

Here is Hughes’ graph for propofol. Look at the CSHT at 4-8hours.  Now look at the same graphs using the Schnider and Marsh models. What do you notice? Which do you think correlates better with what we see clinically?

• T/F The CSHT for propofol after a 8 hour infusion is around 50 minutes

This is the graph for thiopentone. Have a look and see what happens with the prediction for 24 or 48 hour infusion. This certainly does not correspond with what we know clinically about thiopentone. See if you can work out the answer to the following question:

• T/F In Hughes’ graph, the CSHT for thiopentone increases steeply because it changes to zero order kinetics

The following is more of a question for a viva, as it does not have a simple answer:

Remifentanil is a better drug than oxycodone because it has a much shorter CSHT

BT_GS 1.30 Compartmental Modelling

BT_GS 1.30 Describe and compare the pharmacokinetics of intravenous induction and sedative agents, the factors which affect recovery from intravenous anaesthesia and the clinical implications of these differences

Pharmacokinetics of intravenous drugs is an important topic in the Primary. The following questions are based on standard compartmental modelling. You should have a solid understanding of the basic models, even if real life is more complicated.

The links are to an interactive page for compartmental models. If you can’t see the whole graph on the page, try making the page narrower.

Effect Site Concentrations, (Basic, Important)

These two questions are basic and important.

Here is a graph of “Effect site concentrations” after a bolus dose of propofol. Click on the 2x dose button to see what happens if you give a bigger dose.

• T/F Doubling the dose of propofol raises the effect site concentration by a factor of ln(2)

• T/F Doubling the dose of propofol speeds the time to peak effect

Compartment Modelling (Basic, Important)

A three compartment model can be expressed by the equation

Ct = Ae-αt + Be-βt + Ce-ɣt

Look at the graphs here. Display them as both linear and semi-log graphs. How can the constants α, β & ɣ be calculated?

• T/F The constants α, β & ɣ are best calculated using a linear graph.

Look at the plasma concentration time graphs for two different models of Ketamine. Now look at the graphical display of the two models, Perrson and Olofson. You have probably not seen a 2D graphical comparison of models before, but the following concept is also basic and important.

• T/F The compartments in compartmental models refer to physical body compartments.

ke0 (Hard, Important)

ke0 is quite a difficult concept.  t1/2ke0 is confusing because it has no simple relationship to any time that we use clinically. Do not conflate this with Time to Peak Effect!

Look at the different ke0 values for the Schnider and Marsh model for propofol.

• T/F The value for t1/2ke0 is a constant for any given drug

So why is it called t1/2ke0 if it doesn’t tell you the time to peak effect? It is the half life of the movement of drug to the hypothetical effect site. This movement is also affected by the plasma concentration, which in turn is affected by the other half lives. The calculation of time to peak effect involves a complicated function of all of them. TTPE is obviously a fixed property of the drug, so this means the ke0 is affected by the other half lives. Each ke0 is therefore specific to the model it has been calculated for. You cannot compare them between models.

 

BT_GS 1.10 Describe the mechanisms of drug clearance and how physiological and pathological disturbance may effect these

T/F Liver cirrhosis have little effect on the clearance of drugs with a high extraction ratio.

T/F In the obstetric patient, the placenta contributes to clearance of certain drugs.

T/F The infusion rate to maintain a given drug concentration = clearance x volume of distribution.

T/F Drug clearance is the product of cardiac output and hepatic extraction ratio.

T/F Cytochrome P450 enzymes are membrane-bound proteins found in fragments of endoplasmic reticulum.

Therapeutic Drug Monitoring

BT_GS 1.13, Explain clinical drug monitoring with regard to peak and trough concentrations, minimum therapeutic concentration and toxicity

bloodtest

Quite a difficult topic to find good references for in the referenced texts. See here for some suggestions for reading.

T/F Therapeutic drug monitoring is useful for drugs being given for prophylaxis rather than treatment

T/F For therapeutic drug monitoring to be useful there should be a relationship between plasma concentration and effect

T/F It is the total plasma concentration of a drug which correlates best with side effects and toxicity

T/F Therapeutic drug monitoring is useful when it is difficult to distinguish between lack of therapeutic effect and toxicity

T/F Therapeutic drug monitoring is useful when the predominant action of a drug is through an active metabolite.

Drug Metabolism

BT_GS 1.11  Describe the mechanisms of hepatic and non-hepatic metabolism of drugs….

 

T / F   a phase 1 reaction exposes a polar group on the parent molecule, rendering it more water soluble

T / F  all phase 1 reactions are catalysed by the CYP450 enzymes

T / F  adding (conjugating) glucuronide to the parent molecule is an example of a phase 2 reaction

T / F  phase 2 reactions decrease the activity of the parent compound

T / F  CYP2D6 metabolises codeine to morphine – this enzyme is absent in 1% of caucasians

 

Is pharmacogenetic testing the “new frontier” of pharmacology? Your patients might have seen websites like this one from the Mayo clinic. Some patients are already coming to hospital with their “genetic printout” stating which drugs they should have!

BT_PM 1.17 Pharmacokinetics of intravenous opioids and clinical relevance

I am not a massive fan on memorising a whole lot of numbers for the sake of it – boring!!

However, sometimes these pesky numbers can actually help us guide clinical practice and, in that situation, they take on a whole new level of relevance. The pharmacokinetics of opioids are a case in point.

IMG_0248

Hopefully no opioids in this handbag (although to be honest, I couldn’t be sure) Cottesloe, WA

BT_PM 1.17 Describe the pharmacokinetics of intravenous opioids and their clinical applications

The high lipid solubility of fentanyl confers a long duration of action when given intrathecally  TRUE/FALSE

The rapid speed on onset of alfentanil is primarily due to its low pKa  TRUE/FALSE

Duration of action of remifentanil is determined by its elimination half life   TRUE/FALSE

The terminal elimination half life of morphine and fentanyl is similar   TRUE/FALSE

Active metabolites of both morphine and pethidine contribute to the duration of analgesic effect   TRUE/FALSE

BT_GS 1.12 Context sensitive half time

A topical area for us as we often run intra-operative infusions of drugs, sometimes for quite long periods of time!

The topic is not brilliantly covered in that many books. Pharmacology and Physiology for Anaesthesia Ch 2 by Hemmings and Egan, is a great chapter full stop and does discuss the topic. This article in BJA Education also gives a good little summary.

IMG_0478

Another photo from beautiful Tasmania today, Wineglass Bay

The context sensitive half time of a drug will never be longer than its elimination half life   TRUE/FALSE

The “context” is the duration of the infusion   TRUE/FALSE

Following cessation an infusion, the fall in plasma concentration is proportional to elimination of drug from the body  TRUE/FALSE

Prolongation of the half time, as the duration of the infusion increases, is directly proportional to the lipid solubility of the drug  TRUE/FALSE

Context sensitive half time is a term that only applies to multi compartmental models   TRUE/FALSE

Forensic pharmacokinetics

Have a look at this document – Trial of Conrad Murray  – a most fascinating read which illustrates some interesting pharmacokinetics. There are two expert witness reports in this document – read the brief letter from Paul White to Mr Flanagan first, ponder the below questions, then read the prolix submission from Steven Schafer where you’ll find a lot more detail and most of the answers.

 

A range of propofol concentrations (2.6-4.1 mcg/ml)  was given for the circulatory system – why would there be differing propofol concentrations in different sampling sites?

The propofol concentration in the stomach at autopsy was 1.9 mcg/ml. Why? Do you think he ingested the drug with fruit juice as Dr White speculates?

The lignocaine concentration in the femoral vein was 0.84 mcg/ml and in the stomach 23 mcg/ml. Can you explain this?

 

 

 

 

 

BT GS 1.12 Explain and describe the clinical application of concepts related to intravenous and infusion kinetics

Admittedly, this is a rather dry topic.  It is of unequivocal importance to anaesthetists however as our practice revolves around giving drugs that have potent pharmacodynamics effects with rapid onset and offset of action.

Regarding the time to peak effect (TTPE):

Is indicated on a plasma time curve for a bolus dose where the effect site curve crosses the plasma concentration curve TRUE/FALSE

Will be relatively short for any drug that rapidly redistributes TRUE/FALSE

Will be relatively short for drugs with a large keo TRUE/FALSE

Will always be longer than the t ½ keo TRUE/FALSE

Is considered to be a dose insensitive parameter TRUE/FALSE