2019B Question 09

Using ropivacaine and lignocaine as examples, explain the pharmacokinetic principles that affect speed of onset and duration of action of local anaesthetics.

Examiner Report

52.4% of candidates achieved a pass in this question.

The major domains assessed in this question were:

  • Onset: Diffusion principles and effect of pH and pKa on ionisation,
  • Offset: The effect of physical properties and the effect of vasoconstriction and blood flow.

Common problems were not answering both halves of the question or listing properties without indicating the effect of the property. It should be noted that additives affect lignocaine and ropivacaine differently. pKa is not the pH below which a drug is ionised, but rather the pH at which 50% of the drug is ionised.

Model Answer

Structure:

  • Introduction
  • Onset
    • Rate of passage
    • MLAC
  • Duration

Introduction

Term Details
Local anaesthetic - Antagonist at axonal voltage-gated Na+ channel (VDNaC)
Drug path

- Interstitium → Axoplasm

- Only unionised drug diffuses readily

- Ionised > unionised drug enters receptor

- ICF > ECF drug enters receptor

Onset

Determinants of speed of onset:

  • Rate of passage into axoplasm
  • Minimum local analgesic concentration (MLAC)

Rate of Passage

Factor Rate increased with:
Fick’s Law
↑ C1

↑ Concentration (major factor)

e.g. 10% cf. 1% lignocaine

↓ C2 ↑ Tissue protein binding
↑ Area ↑ Volume injected
↓ Thickness

- ↑ Size of nerve (e.g. Sciatic cf. median)

- ↑ Connective tissue (e.g. Sciatic cf. median)

 - Added hyaluronidase → ↓ Effective thickness

- ↓ Distance from centre of bundle (i.e. proximal affected before distal)

↑ Diffusion Coefficient

- ↑ % Unionised: (major factor)

 - Drug: Ligno 25% cf. ropiv 15%

 - Additive: e.g. HCO3- → ↑ % unionised

 - Patient: e.g. Abscess → Acidosis → ↓↓ % unionised

- ↑ Lipid solubility (ropiv 300x cf. ligno 150x)

- ↓ Molecular weight (ligno 234g.mol-1 cf. bupiv 274g.mol-1)

Minimum Local Analgesic Concentration

Factor Decreased (i.e. Sensitivity increased) with:
Nerve Sensitivity

- Myelination (3 consecutive nodes of Ranvier ≈ 1cm)

- ↑ Frequency of action potential

- ↓ Nerve diameter → ↓ Ratio surface area : Axon unit volume

Order of decreasing sensitivity: B > C > Aδ > Aγ > Aβ > Aα (sensory 2x motor)

Patient

- ↑ Tissue pH

- Pregnancy

Drug - ↑ Potency (ropiv 8x ligno 2x)
(correlates with ↑ lipid solubility)
Additives

- Opioid

- α2 agonist

Duration

Introduction

Determinants of rate of offset:

  • Maximum concentration in axoplasm
  • Rate of removal from axoplasm
  • Minimal local anaesthetic concentration (MLAC)

Maximum Concentration

Increased with:

  • ↑ Concentration of solution
  • ↑ Volume injected

Rate of Removal

Factor Removal slowed with:
Fick’s Law
↓ C1

- ↑ VDNaC affinity → ↓ Dwell time (ropiv > ligno)

- ↑ Tissue protein binding (ropiv > ligno) (major factor)

↑ C2

Drug:

- Intrinsic vasoconstriction (ropiv constrict cf. ligno dilate)

- Added adrenaline

- Slow metabolism → Slow removal
(both ropiv and ligno metabolised by amidases cf. plasma cholinesterase)

Patient:

- Low intrinsic blood flow (decreasing order: Tracheal / intercostal / caudal / paracervical / epidural / plexus / peripheral nerve / subcut)

- Tissue hypoperfusion (↓ if heart failure, shock; ↑ if pregnancy, neonate)

- Slow metabolism (e.g. Neonate)

↓ Area
↑ Thickness

- ↑ Size of nerve (e.g. Sciatic cf. median)

- ↑ Connective tissue (e.g. Sciatic cf. median)

- ↓ Distance from centre of bundle (i.e. distal cf. proximal target)

↓ Diffusion coeff

- ↓ Lipid solubility (ligno 150x cf. ropiv 300x)

- ↑ Molecular weight

- ↓ % unionised (ropiv 15% cf. lignocaine 25%); or ↓ tissue pH

Minimum Local Analgesic Concentration

As above.


Last updated 2021-08-23

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