BT_GS 1.9 Describe factors influencing the distribution of drugs (for example … protein binding …)

This post will be on local anaesthetic pharmacology, with reference to protein binding.

Many trainees immediately think here of the plasma protein alpha1 acid glycoprotein (AAG)… because local anaesthetics are bases. However, does binding to AAG have anything to do with the duration of effect of local anaesthetics?

The answer is no – because the action of local anaesthetics does not depend on their distribution within the central compartment – this is because we don’t give them intravenously!! (See Note 1) The % plasma protein binding is therefore irrelevant…..once a molecule of LA has diffused away from the nerve, and entered the bloodstream, it is no longer able to have any interaction with the nerve.

Actually, there is some relevance to the %PPB… because “this correlates with  the degree of protein binding on the extracellular axonal membrane” (Evers & Maze 2nd ed p. 578). Obviously, these cell membrane proteins are not AAG. But if LA binds to the cell membrane ones, it is being held in close proximity to the nerve (like a depot), and from this location can diffuse through the cell membrane. Therefore this prolongs duration of action.

It’s tempting to extrapolate this one step further, and think that PPB might correlate with LA binding to the inside of the sodium channel (after all, the sodium channel is just a big protein). However “it does not appear that the degree of local anaesthetic protein binding correlates with increased affinity to the protein structure of the VGSC. Studies have suggested that the binding and dissociation of local anaesthetic molecules from the VGSC occurs in a matter of seconds, irrespective of the degree of protein binding” (Evers & Maze 2nd ed, p.578).

T/F  when doing a nerve block, the plasma protein binding of a local anaesthetic is important because only the unbound portion can penetrate the nerve

T/F  plasma protein binding correlates with tissue protein binding, and therefore duration of action

T/F  tissue protein binding is the most important factor in determining the duration of action of a LA block

T/F  “tissue protein binding” (above) is referring to binding within the sodium channel

T/F  PPB of lignocaine is about 65%, and is about 95% for bupivacaine and ropivacaine

Note 1
Actually, we do give some local anaetshetics intravenously. Lignocaine can be given IV, both for pain management, and as an antiarrhythmic. Also, a Bier’s block (intravenous regional anaesthetic) requires the IV injection of prilocaine (usually), with a tourniquet insitu.
However, almost all of the uses of LA are not by IV injection – so you shouldn’t think of LA pharmacology for nerve blocks in terms of the usual IV kinetics.

2019.1 SAQ 8 – local anaesthetic toxicity

20 mL of 1% ropivacaine is inadvertently administered intravenously over 15 seconds to a 60 year old, 60kg woman.  Describe the potential complications and mechanisms of this.  Do not discuss treatment.

Inadvertent iv administration of local anaesthetic is something that we all want to avoid. This question asks you how and why it is a problem?

The answer to all of these statements can be found in Hemming’s and Egan’s book which has quite a nice section on the topic.

The maximum safe dose of ropivacaine is 2ml/kg T/F

Sodium channels in the heart and CNS are blocked by local anaesthetic drugs T/F

Initial CNS effects are due to blockade of inhibitory pathways T/F

Excitatory CNS effects progress to coma and apnoea as plasma levels of ropiviacaine increase T/F

Cardiovascular effects are due to both direct effects on the heart and effects on the CNS T/F

Cardiac action potential duration is increased by toxic doses of ropivacaine T/F

Malignant arrhythmias are usually atrial in nature T/F

In toxic doses, ropivacaine causes vasodilation T/F

BT_RA 1.15 Describe how the baricity of the agents used and positioning of patients may affect the extent of block in spinal anaesthesia

T/F  “baricity” refers to the density of a liquid in mg/L

T/F  “baricity” and “specific gravity” are the same thing

T/F  the baricity of local anaesthetic can be increased by adding glucose

T/F  “heavy” bupivacaine contains 8% glucose (8 mg glucose per mL)

T/F  the advantage of “heavy” bupivacaine is a more reliable spinal block, that ascends to a higher level than “plain”

T/F  if a spinal is injected with the patient in the lateral position, the use of “heavy” bupivacaine will result in a denser block on the dependent side

BT_RA 1.14 Describe factors influencing dose and choice of anaesthetic agents for spinal anaesthesia

Something with many spines…. (Ecuador)

This is a very clinical LO, and something that you have probably thought about when performing spinals yourselves. The LO also talks about epidurals, but I think we can tackle that in a separate post.

Why is it that we use bupivacaine almost exclusively as our local anaesthetic in the subarachnoid space?

Miller’s Anesthesia 8e Ch 56 gives a detailed description of this topic.

BT_RA 1.14 Describe factors influencing dose and choice of anaesthetic agents for spinal anaesthesia and epidural anaesthesia/analgesia

If other factors are kept constant, an increased dose of local anaesthetic (LA) will usually result in a higher block T/F

Use of a hyperbaric LA solution increases the ease of obtaining a saddle block T/F

Transient neurological symptoms have been associated with the use of lignocaine with 5% dextrose T/F

The addition of adrenaline to LA in a spinal anaesthetic may improve analgesia by direct α2 agonism  T/F

The addition of clonidine to a spinal improves analgesia without prolonging motor block T/F

 

Oops

I drew up some saline from the drawer in the birth suite to flush the cannula before putting in an epidural.

When I checked again I found that the drawer was filled with a mixture of saline and lignocaine.

 

 

 

 

 

 

BT_RA1.3  Discuss the pharmacology of local anaesthetic agents including:
· Mechanisms of action
· Comparative pharmacology of different agents
· Toxicity
· Use of adjuvant agents to enhance the quality or extend duration of block
· Pharmacokinetics of drugs administered in the epidural and subarachnoid space

 

 

 

 

 

If I had given the 20mls as an intravenous bolus:

T/F The best volume of distribution to estimate the peak plasma concentration would be V area.

T/F The most likely arrhythmia to occur would be Ventricular Fibrillation

T/F Seizures occur at a plasma concentration of 5µg/ml

T/F Cardiac arrhythmias occur at a plasma concentration of around 2 times that which cause seizures

T/F Lignocaine causes dose dependent negative inotropy

Bonus questions:

Why is bupivacaine more cardiotoxic than lignocaine?

Is ropivacaine less toxic than bupivacaine?

Why should you treat the seizures?

2017.1 : SAQ 12

Discuss the physiological consequences of total spinal anaesthesia caused by intrathecal administration of 20ml of  2% lignocaine at the L3/4 level. (Do not include management)

BT_RA 1.2

A great question to demonstrate understanding of the physiological consequences of neuraxial blockade. The effects can all be deduced from your knowledge of physiology and pharmacology. However there is a most excellent article in AIC(1974) in which TI Evans, a Victorian anaesthetist, administered 30-40ml of 1% lignocaine intrathecally at the lumbar level in 100 patients. He proceeded to tilt the table 10 to 15 degrees head down and administer oxygen until vocal cord paralysis and unconsciousness developed and he intubated them. There were excellent conditions for abdominal surgery. The curious can access this work online through the college library, as a bonus the same issue (2) has quite a nice article on electrical safety as well.

This will cause bradycardia TRUE/FALSE

The patient will have dilated gut TRUE/FALSE

The patient will become hyperthermic TRUE/FALSE

The patient will have dilated pupils TRUE/FALSE

The patient will be unconscious TRUE/FALSE

2017.1 : SAQ 7

Discuss the factors affecting duration of action of a local anaesthetic block to a major peripheral nerve.

BT_RA 1.3

Lot of patient interest out there in you knowing this.

Less lipid soluble drugs have a longer duration of action  TRUE/FALSE

Low protein binding causes a longer duration of action  TRUE/FALSE

Large molecules have a longer duration of action  TRUE/FALSE

Less vascular areas have a longer duration of action  TRUE/FALSE

In an elderly patient there will be a longer duration of action  TRUE/FALSE

Local Anaesthetics Part 2

A bit more on toxicity of local anaesthetics today.

BT_RA1.3  Discuss the pharmacology of local anaesthetic agents including:
· Mechanisms of action
· Comparative pharmacology of different agents
· Toxicity
· Use of adjuvant agents to enhance the quality or extend duration of block
· Pharmacokinetics of drugs administered in the epidural and subarachnoid space

Early excitatory signs of neurotoxicity are due to activation of excitatory interneurons TRUE/FALSE

High foetal plasma concentrations of local anesthetic are a result of higher α1-acid glycoprotein concentrations in the foetus TRUE/FALSE

Methaemaglobinaemia from prilocaine toxicity results in a right shift of the oxygen haemaglobin dissociation curve TRUE/FALSE

All local anesthetics exert dose-dependent negative inotropic action on cardiac muscle TRUE/FALSE

The CNS effects of local anesthetics may contribute to the generation of arrhythmias TRUE/FALSE

Local Anaesthetics

Sometimes whilst studying, I felt like I needed some Novocaine for the soul

Today, local anaesthetics….

BT_RA 1.3 Discuss the pharmacology of local anaesthetic agents including:
· Mechanisms of action
· Comparative pharmacology of different agents
· Toxicity
· Use of adjuvant agents to enhance the quality or extend duration of block
· Pharmacokinetics of drugs administered in the epidural and subarachnoid space

Duration of action of a local anaesthetic is primarily determined by the pKa of the agent  TRUE/FALSE

Increasing the dose of local anaesthetic will increase the duration of action TRUE/FALSE

Benzocaine is only suited to topical anaesthesia due to its lipophilicity TRUE/FALSE

All local anaesthetics EXCEPT ropivicaine cause vasodilation TRUE/FALSE

Adding bicarbonate to a local anaesthetic solution hastens the onset of action TRUE/FALSE