Local Anaesthetics

Produce reversible loss of sensation in a specific area by preventing conduction of action potentials in sensory nerves

Lipophilic aromatic group on one end; amide or ester linkage to hydrophilic secondary or tertiary amine at other end

Drugs which have LA actions include anticonvulsants, antiarhythmics, and some antihistamines

Esters
Cocaine, Amethocaine, Procaine
Relatively unstable
Rapidly hydrolysed by plasma cholinesterase
Para-amino benzoate (metabolite of ester Las) associated with hypersensitivity and allergic reactions

Amides
Lidocaine, bupivicaine, prilocaine
Stable in solution
Usually weak acid pH 4-5.5 (bases combined with HCL)
Slowly broken down by amidases in liver
Hypersensitivity reactions rare

Mode of action
Reversible blockade of sodium channels in conducting neural tissue
Administered as water soluble hydrochlorides (B.HCL)
After injection base released by relative alkalinity of tissues
B.HCL + HCO3 ←→ B + H2CO3 + Cl
Unionised base diffuses into nerve axoplasm where the ↑ acidity (7.3) causes it to partially ionise again
B + H ←→ BH
Ionised base enters into sodium channels from nerve interior and induces a conformational change to stop them opening thus preventing depolarisation
Na channels in open, resting and inactive state. LA affinity higher when in open or inactivated state
LA stabilise all excitable membranes (skeletal, smooth and cardiac)
With myelinated nerve fibres enough LA must be given to block 3 nodes of Ranvier
Thus unmyleinated C fibres (pain) are more sensitive to LA than motor nerves

Onset
pKa

  • LAs are bases, have pKas > 7.4 and are therefore >50% ionised at physiological pH. So the closer a LAs pKa to 7.4 the more unionised (and therefore lipid soluble) it will be and the faster its speed of onset.
Concentration
  • ↑ conc → faster onset (conc gradient).
Potency
Lipid solubility of aromatic group

Duration of action
Protein binding at site of action (↑ binding → ↑ duration of action)
Mass/length of drug (larger → ↑ duration)
Absorption from site (blood flow)
Inherent vasodilator effects (↑ vasodilatation → ↑ absorption – lidocaine > prilocaine)

pKa onset unionised protein duration
Lidocaine 7.9 fast 25% 65% medium
Prilocaine 7.7 fast 55% medium
Bupivicaine 8.1 slow 17% 95% long

Complications

Technique related
Direct neural trauma
Bleeding and haematoma
Intravascular injection
Pneumothorax
Inadvertent epidural/intrathecal injection

Drug related
Sympathetic blockade
Toxicity
  • Immediate/delayed
  • Anaphylactoid (more common with esters)
  • Methaemaglobinaemia (prilocaine)
Toxicity

Contributing factors
Site of injection determines rate of absorption
  • Intercostal > caudal > epidural > brachial plexus > fem/sciatic > subcut
Drug dose and concentration (dilute solution of same dose has lower peak levels)
  • Lignocaine 3mg/kg or 7mg/kg with adrenaline
  • Bupivicaine 2mg/kg
  • Prilocaine 400mg total dose
  • Ropivacaine 150mg total dose
Vasoconstrictors
  • Reduce max concentrations
  • LA cause vasoconstriction in subclinical doses and vasodilatation in clinical doses
pH
  • LA more ionized if acidotic → ↓ binding → ↑ toxicity (more free drug)
Effects
Muscle
  • LAs damage muscle if IM injection (not usually clinical problem)
Prilocaine
  • Methaemoglobinaemia
  • Treat with methylene blue
CNS
Biphasic effect
  • Initial excitation – perioral tingling, light headedness, dizziness, visual and auditory disturbance, fitting – due to inhibitory pathway blocking
  • Generalised depression – coma, resp arrest
CNS signs at much lower dose than needed for cardiac toxicity
CVS
  • Binds to myocardial proteins → ↓ CO (↓ Vmax, HR, long PR, wide QRS) → arrhythmias (VF)
Treatment of toxicity
  • Stop injection
  • ABC
  • Intralipid
CNS
  • Sedation – Propofol/midazolam
CVS
  • Bretyllium for ventricular arhythmias (? Made anymore)

Bupivicaine

pKa 8.1
17% unioized
95% protein bound
Vd 75L
Metabolism phase 2 hepatic
T1/2 180

Lignocaine

pKa 7.9
25% unionized
65% protein bound
Vd 100L
T1/2 100