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
| 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 |
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 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.