NeuroPharm – LA

Master answer

Local anaesthetic

• Lipophilic group attached to ionized group via ester linkage (ester local anaesthetic) or amide group (amide local anaesthetic agents
• MoA
  • Binds to and blocks volatage-gated Na channel on the inner surface of the cell membrane, inhibiting depolarization
  • Increases threshold for depolarization
  • Decreases impulse conduction
  • Action potential abolished
  • Higher affinity for open or inactive Na channels
• Hypercalcaemia stabilizes membrane (Na channels in rested state) reducing efficacy of local anaesthetics
• Hyperkalaemia depolarizes membrane (Na channels in open or inactive state) increasing the efficacty of local anaesthetics

Structure-Activity Relationship

• Ficks law of diffusion
  • Membrane permeation
    • Lipophilicity
    • Small molecular weight
  • Protein binding
    • Can be displaced

Toxicity

• CNS
  • Paraesthesia in lips and tongue
  • Convulsions
  • Sedation
  • Coma
• CVS
  • Arrhythmia

Factors affecting local anaesthetic toxicity

Pharmacokinetics

A

• Dose
  • Lignocaine 3~5mg/kg without adrenaline
  • Ropivacaine 3mg/kg
  • Bupivacaine 3mg/kg
• Route of administration
  • IV
  • Highly vascularized tissues
  • Use of adrenaline decreases toxicity risk

D

• Lipophilicity
  • pK_a – Most LAs 7.9~8.4
    • Low fraction of unionized drug
• Size of drug
• Protein binding
  • If high, less likely to cross BBB
  • However if reaches cardiac myocytes, more likely to bind → prolonged effects

M and E

• Amide anaesthetic longer duration. Hepatic vs. ester metabolism
• Both renally excreted

Patient factors

• pH – will affect ionization state with acidosis reducing LA permeation, however once across the membrane, increased ionization increases LA binding to channel and effect
• Hepatic function
  • Decreased metabolism à prolonged effect
  • Decreased pasma protein à increased free fraction à increased effect
• Renal function
  • Decreased GFR à decreased clearance à prolonged effect

Sakurai 2016

Answer by Sakurai