Local anaesthetics

Class: Local anaesthetic and class 1b antiarrhythmic

Pharmacuetics: colorless liquid, stored in acidic pH to remain soluble. 1% and 2% formulations common.

Dose: max subcut dose 3mg/kg; with adrenaline 7mg/kg. 1mg/kg IV dose for antiarrhythmic effect -> 1mg/kg/hr infusion. CC/CNS ratio 7:1 (plasma level for CNS toxicity << that for CVS toxicity).

A: 35% OBA

D: 0.9L/kg, 70% protein bound

M: Completely hepatically metabolised \(\to\) inactive metabolites

E: No renal elimination. T1/2=15 minutes IV, 1 hour subcut, duration of action \(\approx\) 1 half life

Mechanism:

• Unionized form diffuses across excitable cell membrane \(\to\) becomes ionized in more acidic ICF
• Binds to open state of fast sodium channel \(\to\) stabilize in inactive state
• Use-dependance = more frequent firing \(\to\) more efficacious block

Effects:

• Preferentially affect pain and temperature sensory fibers because C-fibers are unmyelinated
• Regional anaesthsia
• Motor block with higher exposure
• CNS effects - visual disturbamces, perioral numbness, progressing to seizure, coma.
• CVS effects - tachycardia and hypertension \(to\) bradycardia, negative inotropy, vasodilation, arrhythmia. QRS prolongation.

Lidocaine

• Fast onset (<5 minutes)
• Short duration ~1 hour
• CC/CNS 7:1

Bupivicaine

• Slow onset (15 minutes)
• Longest duration ~18 hours
• Most cardiotoxic, CC/CNS 3:1

Ropivacaine

• Slow onset (15 minutes)
• Intermediate duration (~10 hours)
• Medium cardiotoxicity, CC/CNS 5:1

Onset

• Concentration gradient: \(\therefore \ \downarrow\)potency \(\to\) higher dose \(\to\) faster onset
• Optimal pKa: pKa < pH of ECF \(\to\) rapid diffusion into myelin; pKa > pH of ICF \(\to\) ionization in cell (only ionized drug can bind to fast Na channel); alkalosis or coadministration with NaHCO3 \(\to\) faster onset
• Protein binding: drug with low protein binding or hypoalbuminaemia (pregnancy, critical illness) \(\downarrow\)binding \(\to \ \uparrow \Delta C \ \to \) faster onset
• Diffusion distance: small, unmyelinated nerves (C fibers) affected first
• Molecule size: Small molecule \(\to\) rapid diffusion \(\to\) faster onset
• Use-dependance: \(\uparrow\)firing frequency \(\to\) more fast Na channels in open state \(\to \ \uparrow\) drug binding \(\to\) faster onset

Duration

• Concentration gradient:\(\therefore \ \uparrow\)potency \(\to\) lower gradient \(\to\) longer duration
• High pKa (ion traps drug inside cell)
• High lipid solubility (reservoir in myelin)
• High protein binding (reservoir on protein)
• Molecule size: Large molecule \(\to\) slow diffusion away from site
• Metabolism: esters \(\xrightarrow{\text{esterases}}\)inactive \(\therefore\) shorter duration
• Local perfusion: high CO or hyperaemia \(\downarrow\) duration; coadministration of vasopressor \(\uparrow\) duration

Toxicity - patient factors

• Acidosis \(\to \ \uparrow\)ionized fraction \(\to\) ion trapped in plasma
• Extremes of age (less protein binding)
• Pregancy (less protein binding, more site perfusion)
• Hyperkalaemia

Toxicity - drug factors

• Dose
• CC/CNS ratio (e.g. bupivocaine more cardiotoxic)
• Site (e.g. hyperaemic site, epidural \(\to\) more toxic)
• Coadministration of vasopressor (slows systemic update \(\to\) less toxic)