BT_PO 1.119 Describe the mode of action of protamine and potential adverse reactions

Unless you’re doing a cardiac term you won’t have much contact with this drug. However much badness can result from the intemperate use of this drug (even worse if you’ve forgotten to give the heparin in the first place!) so you need to know about it. Most of the important points are covered in the statements below and again I used Goodman and Gilman because I’ve recently bought self a copy. (Also used Stoelting cos there wasn’t much in G&G…annoying)

T/F  Protamine is a polypeptide drug derived from fish sperm and is positively charged

T/F  Protamine should be given slowly to reduce the risk of anaphylaxis

T/F  to antagonise unfractionated heparin the dose is approximately 1mg Protamine per 100 units of heparin

T/F  Protamine doesn’t antagonise LMWH at all

T/F  paradoxically, Protamine can cause an anticoagulant effect itself

T/F Protamine is cleared more rapidly than heparin and this accounts for the ‘heparin rebound’ effect

T/F Protamine is contraindicated in individuals with a seafood allergy

SS_PA 1.53 Describe the changes in the pharmacodynamics of volatile agents, analgesics, opioids and neuromuscular blocking agents in the neonate and the changes that occur with growth and development and the implications for anaesthesia

This is the last paediatric one for a while. However, it’s probably the most relevant one so plenty of questions. Miller has a nice chapter on this (8e Ch93). Given that yesterday’s post was so short, you get some bonus statements today!

When sevoflurane first came out it was heinously expensive compared to halothane and so we weren’t allowed to use it very often at the parsimonious unnamed children’s hospital in Victoria. Halothane inductions took a while (why? and why particularly with spontaneous ventilation?) and the advice was “when you think they are anaesthetised, wait another couple of minutes” before instrumenting the airway. We could use sevoflurane for quick inductions (to save money) but not for the case. Halothane also took a lot longer to wear off than sevoflurane (why?), so the Recovery Room was a quiet, full place. When sevoflurane came into routine use it was often called “screamothane” by the Recovery staff. Why was that?

T/F  MAC of sevoflurane for neonates is about 3.3%

T/F  the incidence of emergence excitement and agitation is higher with sevoflurance than halothane

T/F  the induction dose of propofol should be reduced in infants compared to older children

T/F  TCI propofol should not be used in children because of the risk of propofol infusion syndrome

T/F the required dose of suxamethonium in infants is twice that of older children

Enough of the easy ones, how about these:

T/F  ketamine as a sole anaesthetic agent preserves the gag reflex

T/F  rocuronium can be administered intramuscularly in children

T/F  sugammadex may not be administered to children under 12

And finally, for the real experts:

T/F  clearance of alfentanil is reduced in children compared to adults

T/F  newborns have a slower clearance of morphine than older neonates

BT PO 1.90 Outline the pharmacology of oral hypoglycaemic agents

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Previous posts have addressed insulin preparations, glucagon, corticosteroids and DDAVP so we should complete the diabetic pharmacopeia and consider oral hypogylcaemic agents and parenteral agents other than insulin. Although not a core topic for the primary, knowledge about these drugs is vital with regards to managing them appropriately in the perioperative period.

Having just completed revising the perioperative diabetic medication management guidelines in my hospital I am currently at the peak of my powers with regards to knowledge of these medications. (A similar comment could be made about my knowledge of most things physiological and pharmacological in the week prior to my primary exam…) There’s an awful lot of medications on the market and many of them have been relatively recently added- MIMS has over seventy drug preparations listed.  As an aside I predominantly used the 2015 UK Guideline which is very good and you may be surprised re how many of the agents they recommend to continue to take on the day of surgery including our good friend metformin. This guideline precedes the recent alert by our College regarding SGLT-2 transport inhibitors and euglycaemic ketoacidosis. The recommendation is for this particular class of agents to be withheld THREE days prior to surgery.

The answers to the questions below can be found in Stoelting, a book that I quite like in its current incarnation. (Although it has nothing about SGLT-2 inhibitors in it!)

Lactic acidosis is a common problem seen with metformin use in the perioperative period.  T/F

Acarbose (Glucobay) is a alpha-glucosidase inhibitor.   T/F

Glucagon-Like-Peptide 1 agonists are injected subcutaneously like insulin*.  T/F

Dipeptidyl-Peptidase-4 inhibitors increase insulin secretion and decrease glucagon secretion.  T/F

Rosiglitazone can cause a transaminitis.  T/F

*I may have given you a clue about this one already

Rank the following agents in order from most likely to least likely in terms of causing hypoglycaemia if taken while fasting. To ‘help’ you out I will even tell you the drug class each agent is from.

Exenatide (GLP-1 agonist)

Sitagliptin (DPP-4 inhibitor)

Glipizide (sulfonylurea)

Repaglinide (meglitinide)

Some cool trivia: Exenatide is derived from a hormone found in Gila monster lizard saliva!

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.

 

2018.1 SAQ 12 Neostigmine and sugammadex

Compare and contrast the pharmacology of neostigmine and sugammadex

“Anaesthesia reversal”, as these drugs are referred to on an automated theatre record we used to use, has always stuck me as a funny term – I hope I never have an anaesthetic where either of these two drugs is sufficient to reverse it! These are drugs we give on a daily basis, although sugammadex is used rarely in the institution I work in because of the cost. Is that its only limitation?

You should find these drugs covered adequately in the  pharmacology books on the reading list

BT_GS 1.39 Describe the reversal of neuromuscular blockade using anti- cholinesterase agents, anticholinergics and sugammadex and the physiological effects of reversal

Both neostigmine and sugammadex will reverse all aminosteriod non depolarising muscle relaxants T/F

Sugammadex can be used safely in patients with severe renal impairment (eGFR < 30ml/min) T/F

Unlike neostigmine, sugammadex has no effect on acetylcholine T/F

In a patient with a TOF ratio ≥ 2, equipotent doses of sugammadex and neostigmine with have a similar time to onset of effect T/F

There is a significant risk of oral contraceptive pill failure in patients who have received sugammadex T/F

2018.1 SAQ 8

Outline the pharmacology of intravenous metoprolol.

The use of beta-blockers peri-operatively has been topical for the last few years. There have been conflicting results with large studies, but the evidence has strongly suggested that stopping a patient on long term beta blocker therapy can cause harm.

We are often faced with patients who, for various surgical and hospital reasons, have missed their regular beta blocker dose. This question asks about the pharmacology of intravenous metoprolol, which is one of the more commonly used beta blockers in a theatre environment. We ask this question because we want you to consider why and when you would give this drug, and what the effects of giving this might be.

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A. Metoprolol is a non-selective beta antagonist. TRUE/FALSE

Beta blockers can be categorised as non selective or cardio-selective. The cardio-selective are more potent at blocking beta-1 receptors than beta-2, and are therefore much less likely to trigger bronchospasm. This effect can be overcome with higher doses and even cardio-selective beta blockers can become non-selective at higher doses.

B. The metabolism of metoprolol is reliable and predictable. TRUE/FALSE

Metoprolol is a racemic mixture and exhibits stereo selective metabolism when administered orally. It is dependent on oxidation via CYP2D6. CYP2D6 is absent in approximately 8% of the caucasian population.

C. The intravenous dose of metoprolol is the same as the oral dose. TRUE/FALSE

The oral bioavailability of Metoprolol is 50%. This can go up to 70% if there are repeated doses. The biological half life has a large range but in normal metabolisers is 3-7 hours.

D. Metoprolol is not used in congestive heart failure or ischaemic heart disease, due to its effects on contractility. TRUE/FALSE

Metoprolol is used in coronary vascular disease. Why is this?

E. Metoprolol can be used in Raynaud’s due to the vasodilatory effects. TRUE/FALSE

The beta 2 receptors can be activated and cause bronchodilation. They can also cause vasodilation in the vessels in the gut, skeletal muscle and the kidneys.

2018.1 SAQ 6

BT_GS 1.24 (Inhalational agents – pharmacokinetics)

Describe the washout of sevoflurane from a patient following two hours of general anaesthesia. You may wish to use a graph to illustrate the description.

Anaesthesia is unique in medicine for many reasons, one is our need to control offset of action of drugs as closely as onset. Desired effects become adverse effects once the patient is wheeled out of the operating theatre.

The scale on the abscissa (y axis) of this graph is logarithmic  T/F

This graph is modeled with a single exponential function T/F

High solubility drugs will wash out more quickly than relatively insoluble ones T/F

This graph takes into consideration metabolism of drugs in the liver  T/F

The initial rapid decline is due to washout from well perfused organs such as the heart  T/F

 

2018.1 SAQ 5

BT_PM 1.12 (Opioid receptors)

List the desired and adverse effects of opioids and the corresponding anatomical location of the receptors being activated

Opioids have multiple sites of action and many of their effects are undesirable. These should be considered in your patients, and other analgesic techniques used if harms potentially outweigh benefits.

Opioids can mediate analgesia through presynaptic primary sensory afferents T/F

Opioids can mediate analgesia in the dorsal horn of the spinal cord T/F

Opioids have no supra-spinal mediation of analgesia  T/F

Immunosuppression is an adverse effect of opioids T/F

Biliary spasm is an adverse effect of opioids T/F

Bonus question, definitely not core material in answering this question but interesting. First paragraph of the pethidine entry on wikipedia leads you to the answer but it’s worth considering why the Germans were trying to develop drugs of this class in 1939.

Pethidine can cause mydriasis T/F