2019B09 Using ropivacaine and lignocaine as examples, explain the pharmacokinetic
principles that affect speed of onset and duration of action of local anaesthetics.

 

List:

·      Onset

o   Intro

o   Rate of passage

o   MLAC

·      Duration

o   Intro

o   MLAC

o   Rate of removal

o   MLAC

 

ONSET

 

Intro:

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

Determinants of speed of onset

1.   Rate of passage into axoplasm

2.   Minimum local analgesic concentration (MLAC)

 

1.Rate of passage: factors accelerating it

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)

o Added hyaluronidase -> ↓effective thickness

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

↑Diffusion coeff

·  ↑% unionised: **major factor

o Drug: ligno 25% cf. ropiv 15%

o Additive: e.g. HCO3- -> ↑% unionised

o Patient: e.g. abscess -> acidosis -> ↓↓% unionised

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

·  ↓Molecular weight (ligno 234g/mol cf. bupiv 274g/mol)

 

2.Factors decreasing MLAC = factors increasing sensitivity:

Nerve sensitivity

·  ↓Myelination (3 consecutive nodes of Ranvier 1cm)

·  ↓Frequency of action potential

·  ↓Nerve diameter -> ↓ratio surface area : axon unit volume

 

·  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:

 

Intro:

Drug path

·  Axoplasm -> interstitium -> plasma

·  Only unionised drug diffuses readily

Determinants of rate of offset

1.   Maximum concentration in axoplasm

2.   Rate of removal from axoplasm

3.   Minimal local anaesthetic concentration (MLAC)

 

1.Maximum concentration (factors increasing it)

·         ↑Concentration of solution

·         ↑Volume injected

 

2.Rate of removal (factors slowing it):

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

 

3.Factors decreasing MLAC = factors increasing sensitivity:

As above.

 

 

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